Cell signaling

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cell_signaling 

In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukaryotes. Typically, the signaling process involves three components: the first messenger (the ligand), the receptor, and the signal itself.

In biology, signals are mostly chemical in nature, but can also be physical cues such as pressure, voltage, temperature, or light. Chemical signals are molecules with the ability to bind and activate a specific receptor. These molecules, also referred to as ligands, are chemically diverse, including ions (e.g. Na⁺, K⁺, Ca²⁺, etc.), lipids (e.g. steroid, prostaglandin), peptides (e.g. insulin, ACTH), carbohydrates, glycosylated proteins (proteoglycans), nucleic acids, etc. Peptide and lipid ligands are particularly important, as most hormones belong to these classes of chemicals. Peptides are usually polar, hydrophilic molecules. As such they are unable to diffuse freely across the bi-lipid layer of the plasma membrane, so their action is mediated by a cell membrane bound receptor. On the other hand, liposoluble chemicals such as steroid hormones, can diffuse passively across the plasma membrane and interact with intracellular receptors.

Cell signaling can occur over short or long distances, and can be further classified as autocrine, intracrine, juxtacrine, paracrine, or endocrine. Autocrine signaling occurs when the chemical signal acts on the same cell that produced the signaling chemical. Intracrine signaling occurs when the chemical signal produced by a cell acts on receptors located in the cytoplasm or nucleus of the same cell. Juxtacrine signaling occurs between physically adjacent cells. Paracrine signaling occurs between nearby cells. Endocrine interaction occurs between distant cells, with the chemical signal usually carried by the blood.

Receptors are complex proteins or tightly bound multimer of proteins, located in the plasma membrane or within the interior of the cell such as in the cytoplasm, organelles, and nucleus. Receptors have the ability to detect a signal either by binding to a specific chemical or by undergoing a conformational change when interacting with physical agents. It is the specificity of the chemical interaction between a given ligand and its receptor that confers the ability to trigger a specific cellular response. Receptors can be broadly classified into cell membrane receptors and intracellular receptors.

Diagram of G-protein coupled reception

Cell membrane receptors can be further classified into ion channel linked receptors, G-Protein coupled receptors and enzyme linked receptors.

• Ion channels receptors are large transmembrane proteins with a ligand activated gate function. When these receptors are activated, they may allow or block passage of specific ions across the cell membrane. Most receptors activated by physical stimuli such as pressure or temperature belongs to this category.
• G-protein receptors are multimeric proteins embedded within the plasma membrane. These receptors have extracellular, trans-membrane and intracellular domains. The extracellular domain is responsible for the interaction with a specific ligand. The intracellular domain is responsible for the initiation of a cascade of chemical reactions which ultimately triggers the specific cellular function controlled by the receptor.
• Enzyme-linked receptors are transmembrane proteins with an extracellular domain responsible for binding a specific ligand and an intracellular domain with enzymatic or catalytic activity. Upon activation the enzymatic portion is responsible for promoting specific intracellular chemical reactions.

Intracellular receptors have a different mechanism of action. They usually bind to lipid soluble ligands that diffuse passively through the plasma membrane such as steroid hormones. These ligands bind to specific cytoplasmic transporters that shuttle the hormone-transporter complex inside the nucleus where specific genes are activated and the synthesis of specific proteins is promoted.

The effector component of the signaling pathway begins with signal transduction. In this process, the signal, by interacting with the receptor, starts a series of molecular events within the cell leading to the final effect of the signaling process. Typically the final effect consists in the activation of an ion channel (ligand-gated ion channel) or the initiation of a second messenger system cascade that propagates the signal through the cell. Second messenger systems can amplify or modulate a signal, in which activation of a few receptors results in multiple secondary messengers being activated, thereby amplifying the initial signal (the first messenger). The downstream effects of these signaling pathways may include additional enzymatic activities such as proteolytic cleavage, phosphorylation, methylation, and ubiquitinylation.

Signaling molecules can be synthesized from various biosynthetic pathways and released through passive or active transports, or even from cell damage.

Each cell is programmed to respond to specific extracellular signal molecules, and is the basis of development, tissue repair, immunity, and homeostasis. Errors in signaling interactions may cause diseases such as cancer, autoimmunity, and diabetes.

Taxonomic range

In many small organisms such as bacteria, quorum sensing enables individuals to begin an activity only when the population is sufficiently large. This signaling between cells was first observed in the marine bacterium Aliivibrio fischeri, which produces light when the population is dense enough. The mechanism involves the production and detection of a signaling molecule, and the regulation of gene transcription in response. Quorum sensing operates in both gram-positive and gram-negative bacteria, and both within and between species.

In slime molds, individual cells aggregate together to form fruiting bodies and eventually spores, under the influence of a chemical signal, known as an acrasin. The individuals move by chemotaxis, i.e. they are attracted by the chemical gradient. Some species use cyclic AMP as the signal; others such as Polysphondylium violaceum use a dipeptide known as glorin.

In plants and animals, signaling between cells occurs either through release into the extracellular space, divided in paracrine signaling (over short distances) and endocrine signaling (over long distances), or by direct contact, known as juxtacrine signaling such as notch signaling. Autocrine signaling is a special case of paracrine signaling where the secreting cell has the ability to respond to the secreted signaling molecule. Synaptic signaling is a special case of paracrine signaling (for chemical synapses) or juxtacrine signaling (for electrical synapses) between neurons and target cells.

Extracellular signal

Synthesis and release

Different types of extracellular signaling

Many cell signals are carried by molecules that are released by one cell and move to make contact with another cell. Signaling molecules can belong to several chemical classes: lipids, phospholipids, amino acids, monoamines, proteins, glycoproteins, or gases. Signaling molecules binding surface receptors are generally large and hydrophilic (e.g. TRH, Vasopressin, Acetylcholine), while those entering the cell are generally small and hydrophobic (e.g. glucocorticoids, thyroid hormones, cholecalciferol, retinoic acid), but important exceptions to both are numerous, and the same molecule can act both via surface receptors or in an intracrine manner to different effects. In animal cells, specialized cells release these hormones and send them through the circulatory system to other parts of the body. They then reach target cells, which can recognize and respond to the hormones and produce a result. This is also known as endocrine signaling. Plant growth regulators, or plant hormones, move through cells or by diffusing through the air as a gas to reach their targets. Hydrogen sulfide is produced in small amounts by some cells of the human body and has a number of biological signaling functions. Only two other such gases are currently known to act as signaling molecules in the human body: nitric oxide and carbon monoxide.

Exocytosis

Exocytosis is the process by which a cell transports molecules such as neurotransmitters and proteins out of the cell. As an active transport mechanism, exocytosis requires the use of energy to transport material. Exocytosis and its counterpart, endocytosis, the process that brings substances into the cell, are used by all cells because most chemical substances important to them are large polar molecules that cannot pass through the hydrophobic portion of the cell membrane by passive transport. Exocytosis is the process by which a large amount of molecules are released; thus it is a form of bulk transport. Exocytosis occurs via secretory portals at the cell plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structures at the cell plasma membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

In the context of neurotransmission, neurotransmitters are typically released from synaptic vesicles into the synaptic cleft via exocytosis; however, neurotransmitters can also be released via reverse transport through membrane transport proteins.

Types of Cell Signaling

Autocrine

Differences between autocrine and paracrine signaling

Autocrine signaling involves a cell secreting a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell itself. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.

Intracrine

In intracrine signaling, the signaling chemicals are produced inside the cell and bind to cytosolic or nuclear receptors without being secreted from the cell. The intracrine signals not being secreted outside of the cell is what sets apart intracrine signaling from the other cell signaling mechanisms such as autocrine signaling. In both autocrine and intracrine signaling, the signal has an effect on the cell that produced it.

Juxtacrine

Juxtacrine signaling is a type of cell–cell or cell–extracellular matrix signaling in multicellular organisms that requires close contact. There are three types:

This image displays the different types of cell signaling

1. A membrane ligand (protein, oligosaccharide, lipid) and a membrane protein of two adjacent cells interact.
2. A communicating junction links the intracellular compartments of two adjacent cells, allowing transit of relatively small molecules.
3. An extracellular matrix glycoprotein and a membrane protein interact.

Additionally, in unicellular organisms such as bacteria, juxtacrine signaling means interactions by membrane contact. Juxtacrine signaling has been observed for some growth factors, cytokine and chemokine cellular signals, playing an important role in the immune response. Juxtacrine signalling via direct membrane contacts is also present between neuronal cell bodies and motile processes of microglia both during development, and in the adult brain.

Paracrine

This image depicts paracrine signaling, where a secretory cell releases signaling molecules that diffuse and trigger cellular responses in nearby target cells

In paracrine signaling, a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance (local action), as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

Paracrine signals such as retinoic acid target only cells in the vicinity of the emitting cell. Neurotransmitters represent another example of a paracrine signal.

Some signaling molecules can function as both a hormone and a neurotransmitter. For example, epinephrine and norepinephrine can function as hormones when released from the adrenal gland and are transported to the heart by way of the blood stream. Norepinephrine can also be produced by neurons to function as a neurotransmitter within the brain. Estrogen can be released by the ovary and function as a hormone or act locally via paracrine or autocrine signaling.

Although paracrine signaling elicits a diverse array of responses in the induced cells, most paracrine factors utilize a relatively streamlined set of receptors and pathways. In fact, different organs in the body - even between different species - are known to utilize a similar sets of paracrine factors in differential development. The highly conserved receptors and pathways can be organized into four major families based on similar structures: fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TGF-β superfamily. Binding of a paracrine factor to its respective receptor initiates signal transduction cascades, eliciting different responses.

Endocrine

This image displays endocrine signaling, the process by which endocrine glands produce hormones that are released into the bloodstream, allowing them to travel to distant target cells and bind to specific receptors, triggering a cellular response.

Endocrine signals are called hormones. Hormones are produced by endocrine cells and they travel through the blood to reach all parts of the body. Specificity of signaling can be controlled if only some cells can respond to a particular hormone. Endocrine signaling involves the release of hormones by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems. In humans, the major endocrine glands are the thyroid gland and the adrenal glands. The study of the endocrine system and its disorders is known as endocrinology.

Receptors

Main article: Receptor (biochemistry)

Transmembrane receptor working principle

Cells receive information from their neighbors through a class of proteins known as receptors. Receptors may bind with some molecules (ligands) or may interact with physical agents like light, mechanical temperature, pressure, etc. Reception occurs when the target cell (any cell with a receptor protein specific to the signal molecule) detects a signal, usually in the form of a small, water-soluble molecule, via binding to a receptor protein on the cell surface, or once inside the cell, the signaling molecule can bind to intracellular receptors, other elements, or stimulate enzyme activity (e.g. gasses), as in intracrine signaling.

Signaling molecules interact with a target cell as a ligand to cell surface receptors, and/or by entering into the cell through its membrane or endocytosis for intracrine signaling. This generally results in the activation of second messengers, leading to various physiological effects. In many mammals, early embryo cells exchange signals with cells of the uterus. In the human gastrointestinal tract, bacteria exchange signals with each other and with human epithelial and immune system cells. For the yeast Saccharomyces cerevisiae during mating, some cells send a peptide signal (mating factor pheromones) into their environment. The mating factor peptide may bind to a cell surface receptor on other yeast cells and induce them to prepare for mating.

Cell surface receptors

See also: Ligand (biochemistry) and Receptor–ligand kinetics

Cell surface receptors play an essential role in the biological systems of single- and multi-cellular organisms and malfunction or damage to these proteins is associated with cancer, heart disease, and asthma. These trans-membrane receptors are able to transmit information from outside the cell to the inside because they change conformation when a specific ligand binds to it. There are three major types: Ion channel linked receptors, G protein–coupled receptors, and enzyme-linked receptors.

Ion channel linked receptors

The AMPA receptor bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, PDB: 3KG2​

Ion channel linked receptors are a group of transmembrane ion-channel proteins which open to allow ions such as Na⁺, K⁺, Ca²⁺, and/or Cl⁻ to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.

When a presynaptic neuron is excited, it releases a neurotransmitter from vesicles into the synaptic cleft. The neurotransmitter then binds to receptors located on the postsynaptic neuron. If these receptors are ligand-gated ion channels (LICs), a resulting conformational change opens the ion channels, which leads to a flow of ions across the cell membrane. This, in turn, results in either a depolarization, for an excitatory receptor response, or a hyperpolarization, for an inhibitory response.

These receptor proteins are typically composed of at least two different domains: a transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location (an allosteric binding site). This modularity has enabled a 'divide and conquer' approach to finding the structure of the proteins (crystallising each domain separately). The function of such receptors located at synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands, by channel blockers, ions, or the membrane potential. LICs are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels.

G protein–coupled receptors

A G Protein-coupled receptor within the plasma membrane

G protein-coupled receptors are a large group of evolutionarily-related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. The G-protein acts as a "middle man" transferring the signal from its activated receptor to its target and therefore indirectly regulates that target protein. Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (Rhodopsin-like family). They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed.

G protein-coupled receptors are found only in eukaryotes, including yeast, choanoflagellates, and animals. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. G protein-coupled receptors are involved in many diseases.

There are two principal signal transduction pathways involving the G protein-coupled receptors: cAMP signal pathway and phosphatidylinositol signal pathway. When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G protein by exchanging the GDP bound to the G protein for a GTP. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (G_αs, G_αi/o, G_αq/11, G_α12/13).

G protein-coupled receptors are an important drug target and approximately 34% of all Food and Drug Administration (FDA) approved drugs target 108 members of this family. The global sales volume for these drugs is estimated to be 180 billion US dollars as of 2018. It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of pharmaceutical research.

Enzyme-linked receptors

VEGF receptors are a type of enzyme-coupled receptors, specifically tyrosine kinase receptors

Enzyme-linked receptors (or catalytic receptors) are transmembrane receptors that, upon activation by an extracellular ligand, causes enzymatic activity on the intracellular side. Hence a catalytic receptor is an integral membrane protein possessing both enzymatic, catalytic, and receptor functions.

They have two important domains, an extra-cellular ligand binding domain and an intracellular domain, which has a catalytic function; and a single transmembrane helix. The signaling molecule binds to the receptor on the outside of the cell and causes a conformational change on the catalytic function located on the receptor inside the cell. Examples of the enzymatic activity include:

• Receptor tyrosine kinase, as in fibroblast growth factor receptor. Most enzyme-linked receptors are of this type.
• Receptor protein serine/threonine kinase, as in bone morphogenetic protein
• Guanylate cyclase, as in atrial natriuretic factor receptor

Intracellular receptors

Intracellular receptors exist freely in the cytoplasm, nucleus, or can be bound to organelles or membranes. For example, the presence of nuclear and mitochondrial receptors is well documented. The binding of a ligand to the intracellular receptor typically induces a response in the cell. Intracellular receptors often have a level of specificity, this allows the receptors to initiate certain responses when bound to a corresponding ligand. Intracellular receptors typically act on lipid soluble molecules. The receptors bind to a group of DNA binding proteins. Upon binding, the receptor-ligand complex translocates to the nucleus where they can alter patterns of gene expression.

Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen (group NR3A) and 3-ketosteroids (group NR3C). In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.

Mechanisms of Receptor Down-Regulation

Further information: Downregulation and upregulation

Receptor mediated endocytosis is a common way of turning receptors "off". Endocytic down regulation is regarded as a means for reducing receptor signaling. The process involves the binding of a ligand to the receptor, which then triggers the formation of coated pits, the coated pits transform to coated vesicles and are transported to the endosome.

Receptor Phosphorylation is another type of receptor down-regulation. Biochemical changes can reduce receptor affinity for a ligand.

Reducing the sensitivity of the receptor is a result of receptors being occupied for a long time. This results in a receptor adaptation in which the receptor no longer responds to the signaling molecule. Many receptors have the ability to change in response to ligand concentration.

Signal transduction pathways

Further information: Signal transduction and List of signalling pathways

When binding to the signaling molecule, the receptor protein changes in some way and starts the process of transduction, which can occur in a single step or as a series of changes in a sequence of different molecules (called a signal transduction pathway). The molecules that compose these pathways are known as relay molecules. The multistep process of the transduction stage is often composed of the activation of proteins by addition or removal of phosphate groups or even the release of other small molecules or ions that can act as messengers. The amplification of a signal is one of the benefits to this multiple step sequence. Other benefits include more opportunities for regulation than simpler systems do and the fine-tuning of the response, in both unicellular and multicellular organisms.

In some cases, receptor activation caused by ligand binding to a receptor is directly coupled to the cell's response to the ligand. For example, the neurotransmitter GABA can activate a cell surface receptor that is part of an ion channel. GABA binding to a GABA_A receptor on a neuron opens a chloride-selective ion channel that is part of the receptor. GABA_A receptor activation allows negatively charged chloride ions to move into the neuron, which inhibits the ability of the neuron to produce action potentials. However, for many cell surface receptors, ligand-receptor interactions are not directly linked to the cell's response. The activated receptor must first interact with other proteins inside the cell before the ultimate physiological effect of the ligand on the cell's behavior is produced. Often, the behavior of a chain of several interacting cell proteins is altered following receptor activation. The entire set of cell changes induced by receptor activation is called a signal transduction mechanism or pathway.

Key components of a signal transduction pathway (MAPK/ERK pathway shown)

A more complex signal transduction pathway is the MAPK/ERK pathway, which involves changes of protein–protein interactions inside the cell, induced by an external signal. Many growth factors bind to receptors at the cell surface and stimulate cells to progress through the cell cycle and divide. Several of these receptors are kinases that start to phosphorylate themselves and other proteins when binding to a ligand. This phosphorylation can generate a binding site for a different protein and thus induce protein–protein interaction. In this case, the ligand (called epidermal growth factor, or EGF) binds to the receptor (called EGFR). This activates the receptor to phosphorylate itself. The phosphorylated receptor binds to an adaptor protein (GRB2), which couples the signal to further downstream signaling processes. For example, one of the signal transduction pathways that are activated is called the mitogen-activated protein kinase (MAPK) pathway. The signal transduction component labeled as "MAPK" in the pathway was originally called "ERK," so the pathway is called the MAPK/ERK pathway. The MAPK protein is an enzyme, a protein kinase that can attach phosphate to target proteins such as the transcription factor MYC and, thus, alter gene transcription and, ultimately, cell cycle progression. Many cellular proteins are activated downstream of the growth factor receptors (such as EGFR) that initiate this signal transduction pathway.

Some signaling transduction pathways respond differently, depending on the amount of signaling received by the cell. For instance, the hedgehog protein activates different genes, depending on the amount of hedgehog protein present.

Complex multi-component signal transduction pathways provide opportunities for feedback, signal amplification, and interactions inside one cell between multiple signals and signaling pathways.

A specific cellular response is the result of the transduced signal in the final stage of cell signaling. This response can essentially be any cellular activity that is present in a body. It can spur the rearrangement of the cytoskeleton, or even as catalysis by an enzyme. These three steps of cell signaling all ensure that the right cells are behaving as told, at the right time, and in synchronization with other cells and their own functions within the organism. At the end, the end of a signal pathway leads to the regulation of cellular activity. This response can take place in the nucleus or in the cytoplasm of the cell. A majority of signaling pathways control protein synthesis by turning certain genes on and off in the nucleus.

In unicellular organisms such as bacteria, signaling can be used to 'activate' peers from a dormant state, enhance virulence, defend against bacteriophages, etc. In quorum sensing, which is also found in social insects, the multiplicity of individual signals has the potentiality to create a positive feedback loop, generating coordinated response. In this context, the signaling molecules are called autoinducers. This signaling mechanism may have been involved in evolution from unicellular to multicellular organisms. Bacteria also use contact-dependent signaling, notably to limit their growth.

Signaling molecules used by multicellular organisms are often called pheromones. They can have such purposes as alerting against danger, indicating food supply, or assisting in reproduction.

Short-term cellular responses

Brief overview of some signaling pathways (based on receptor families) that result in short-acting cellular responses

Receptor Family	Example of Ligands/ activators (Bracket: receptor for it)	Example of effectors	Further downstream effects
Ligand Gated Ion Channels	Acetylcholine (such as Nicotinic acetylcholine receptor),	Changes in membrane permeability	Change in membrane potential
Seven Helix Receptor	Light (Rhodopsin), Dopamine (Dopamine receptor), GABA (GABA receptor), Prostaglandin (prostaglandin receptor) etc.	Trimeric G protein	Adenylate Cyclase, cGMP phosphodiesterase, G-protein gated ion channel, etc.
Two-component	Diverse activators	Histidine Kinase	Response Regulator - flagellar movement, Gene expression
Membrane Guanylyl Cyclase	Atrial natriuretic peptide, Sea urchin egg peptide etc.	cGMP	Regulation of Kinases and channels- Diverse actions
Cytoplasmic Guanylyl cyclase	Nitric Oxide (Nitric oxide receptor)	cGMP	Regulation of cGMP Gated channels, Kinases
Integrins	Fibronectins, other extracellular matrix proteins	Nonreceptor tyrosine kinase	Diverse response

Regulating gene activity

Brief overview of some signaling pathways (based on receptor families) that control gene activity

Frizzled (special type of 7Helix receptor)	Wnt	Dishevelled, axin - APC, GSK3-beta - Beta catenin	Gene expression
Two-component	Diverse activators	Histidine Kinase	Response Regulator - flagellar movement, Gene expression
Receptor Tyrosine Kinase	Insulin (insulin receptor), EGF (EGF receptor), FGF-Alpha, FGF-Beta, etc. (FGF-receptors)	Ras, MAP-kinases, PLC, PI3-Kinase	Gene expression change
Cytokine receptors	Erythropoietin, Growth Hormone (Growth Hormone Receptor), IFN-Gamma (IFN-Gamma receptor) etc.	JAK kinase	STAT transcription factor - Gene expression
Tyrosine kinase Linked- receptors	MHC-peptide complex - TCR, Antigens - BCR	Cytoplasmic Tyrosine Kinase	Gene expression
Receptor Serine/Threonine Kinase	Activin (activin receptor), Inhibin, Bone-morphogenetic protein (BMP Receptor), TGF-beta	Smad transcription factors	Control of gene expression
Sphingomyelinase linked receptors	IL-1 (IL-1 receptor), TNF (TNF-receptors)	Ceramide activated kinases	Gene expression
Cytoplasmic Steroid receptors	Steroid hormones, Thyroid hormones, Retinoic acid etc.	Work as/ interact with transcription factors	Gene expression

Signal transduction pathways that lead to a cellular response

Notch signaling pathway

Notch-mediated juxtacrine signal between adjacent cells

Notch is a cell surface protein that functions as a receptor. Animals have a small set of genes that code for signaling proteins that interact specifically with Notch receptors and stimulate a response in cells that express Notch on their surface. Molecules that activate (or, in some cases, inhibit) receptors can be classified as hormones, neurotransmitters, cytokines, and growth factors, in general called receptor ligands. Ligand receptor interactions such as that of the Notch receptor interaction, are known to be the main interactions responsible for cell signaling mechanisms and communication. Notch acts as a receptor for ligands that are expressed on adjacent cells. While some receptors are cell-surface proteins, others are found inside cells. For example, estrogen is a hydrophobic molecule that can pass through the lipid bilayer of the membranes. As part of the endocrine system, intracellular estrogen receptors from a variety of cell types can be activated by estrogen produced in the ovaries.

In the case of Notch-mediated signaling, the signal transduction mechanism can be relatively simple. As shown in Figure 2, the activation of Notch can cause the Notch protein to be altered by a protease. Part of the Notch protein is released from the cell surface membrane and takes part in gene regulation. Cell signaling research involves studying the spatial and temporal dynamics of both receptors and the components of signaling pathways that are activated by receptors in various cell types. Emerging methods for single-cell mass-spectrometry analysis promise to enable studying signal transduction with single-cell resolution.

In notch signaling, direct contact between cells allows for precise control of cell differentiation during embryonic development. In the worm Caenorhabditis elegans, two cells of the developing gonad each have an equal chance of terminally differentiating or becoming a uterine precursor cell that continues to divide. The choice of which cell continues to divide is controlled by competition of cell surface signals. One cell will happen to produce more of a cell surface protein that activates the Notch receptor on the adjacent cell. This activates a feedback loop or system that reduces Notch expression in the cell that will differentiate and that increases Notch on the surface of the cell that continues as a stem cell.

Reward theory of attraction

From Wikipedia, the free encyclopedia

The reward theory of attraction states that people are attracted to individuals exhibiting behaviors that are rewarding to them, whom they associate with rewarding events, or have positive, fulfilling interactions with.

Reward theory was originally developed in the research on interpersonal attraction of the 1960s, a precursor to modern romantic love research. In this early context, "attraction" was often defined as "a positive attitude towards a particular person". Romantic love science was not explicitly studied yet in this period of history; the subject was even considered "taboo" for research.

Attraction was initially conceived of as a continuum, with liking being a "mild" form of attraction at one end, and romantic love being a "strong" attraction at the other end. This idea of a continuum started to change in 1970, when Zick Rubin published his distinction between "liking" and "loving". A later distinction was made by Elaine Hatfield between "passionate" and "companionate" love. Passionate love is "a state of intense longing for another" which involves incentive salience ("wanting", or what is attention-grabbing). Companionate love is "the affection we feel for those with whom our lives are deeply entwined" (or "strong liking").

A successor to reward theory is the self-expansion model by Arthur & Elaine Aron in 1986, which conceptualizes reward as "whatever creates expansion of the self". Like reward theory, self-expansion encompasses "mini-theories" of falling in love and long-term relationships, and has been used to explain the process behind "strong attractions" like passionate love, and Dorothy Tennov's concept of limerence.

Another variant on reward theory, and early prevailing approach to attraction was social exchange theory.

A separate area of research was impression formation, which studied those impressions based on knowledge (i.e. information), rather than the emotional reactions (i.e. affect) studied by interpersonal attraction.

Predictors

Early interpersonal attraction research identified five major predictors of "attraction" (defined then as a "positive attitude"). In this early paradigm, it was assumed that falling in love occurs with an exceptionally strong instance of one of these.

• Similarity (as in "birds of a feather flock together") is an idea dating as far back as Aristotle. The most successful research of this type showed a direct relationship between liking and one's attitudinal agreement on a variety of issues (social, political, or artistic). Studies also demonstrated personality similarity among husbands, wives and friends, although it was unclear to what extent such similarity actually caused attraction. It might also be the case that marriage makes a couple more similar over time, or that such similarity is "more perceived than actual". Similarity can be seen as reinforcing in two ways: we would expect to have more positive outcomes from interactions with a similar person, and interacting with a person who has similar attitudes increases the probability of our validation or competence.
• Propinquity (similarity of location) has been found to result in attraction. People who are seated together or live nearby tend to become friends, and the mere exposure effect (e.g. being able to glimpse a fellow student, regardless of similarity) has been shown to elicit attraction.
• Being liked by a person tends to cause liking towards that person in return, also known as the reciprocal liking rule. A study on falling in love found that a sudden attraction was most frequently associated with a person's discovery of another's attraction to them. As one participant describes, "I met [her] in a department store in which she worked. I was looking for sandals and she recognized me and came over [...]. From that moment on, I thought a lot about her; fantasizing relationships, etc."
• Admirable characteristics of another person (especially e.g. physical attractiveness, but also good health, youthfulness, intelligence, mental health, general competence, and so on) can be a source of reward, which is suggested to be derived from the imagined or projected future interactions with the person wherein those characteristics would make the person either reinforcing or punishing. According to the "matching hypothesis", while a person might also prefer a relationship with an extremely attractive person, they would rather not run the risk of rejection either. A more attractive person might try to "do better" with somebody else. Therefore, according to a "marketplace of open competition", one's relationships tend to be limited to those who also have a similar level of attractiveness.
• Social and cultural influences contribute to who people are likely to meet, who they are allowed to associate with, and what characteristics are viewed as attractive and important.

Self-expansion

The self-expansion model summarized

The core of the self-expansion model as we have applied it to love can be oversimplified as the following three principles:

1. People seek to expand the self.
2. One way they seek to do so is by attempting to include others in the self through close relationships.
3. People seek situations and experiences that have become associated with experiences of expansion of the self.

Elaine Aron & Arthur Aron (1996)

Inclusion of the other in the self (IOS) is typically measured with the IOS Scale.

Main article: Self-expansion model

A limitation of early reward theory was that it could not predict exactly what is rewarding, only determine it by observation (i.e. with studies). To solve this, Arthur & Elaine Aron developed the self-expansion model, which specifies reward as "whatever creates expansion of the self". Self-expansion is the human motivation to expand one's physical influence, cognitive complexity, social or bodily identity, and self-awareness. Relationships are a key area for self-expansion then, via "inclusion of the other in the self", where aspects of a partner (e.g. traits, skills, attitudes, resources, abilities, and worldviews) are incorporated into one's own self concept. Self-expansion can also take the form of having new and exciting experiences with a partner.

The Arons revise the definition of "attraction" to mean a desire to enter a close relationship, usually reflected in attitudes or behaviors. According to their theory, attraction arises when opportunities for self-expansion are perceived, and so a "positive attitude" towards a person (the earlier definition) is only a "frequent symptom". Self-expansion is then used to explain the "strong attraction" of romantic love, including intense varieties of passionate love or limerence, when the rate of expansion is rapid and approaches the maximum total possible from all sources. Additionally, self-expansion explains how unrequited love can be a desired experience.

Besides romantic love, opportunities for self-expansion include learning, career, family, friendship, athletics, travel, artistic expression, politics, gossip, religion, and the experience of nature.

The Arons use a value-expectancy approach to determine attraction as the combination of two factors (desirability and probability):

1. Perceived degree of potential expansion of self that is possible through a close relationship with that particular other.
2. Perceived probability of actually obtaining that expansion with other—that is, probability that one could actually form and maintain a close relationship with this particular other.

According to the self-expansion model, attraction would actually seem to result from the opposite of the five predictors (because e.g. similarity would actually seem to minimize self-expansion—resulting in less attraction). Therefore, the Arons propose that these are five preconditions which make a relationship possible, whereas attraction according to self-expansion increases when the opposite conditions are present. For example, a person may be attracted to similarity when it provides the basis for effective communication or predictability, whereas differences provide the basis for self-expansion: new challenges, new experiences, new resources, etc. The Arons interpret study results (some of which did show dissimilarity was attractive) to mean that in their model, similarity is attractive because it increases the probability of a relationship. If a person believes forming a relationship will be easy, then dissimilarity becomes more attractive for self-expansion.

Passion seems to decline when interactions with a love object become frequent, showing that both propinquity and distance can facilitate attraction. Accordingly, in the tradition of medieval romance, the love object was always inaccessible, and modern people still seem to be "obsessed with the unknown, mysterious lover". The violation of social norms could also be an experience for self-expansion "towards greater autonomy, clearer personal values, new social roles, and the like"—as in "the Romeo and Juliet effect", where parental disapproval seems to enhance romantic love.

An fMRI experiment found that neural activity in regions associated with the physical attractiveness of potential alternative romantic partners was diminished when the participants were primed with a recollection of self-expansion in their current relationship. This effect "may be because the current relationship is bolstered by feelings of self-expansion diminishing the relative attractiveness and therefore the incentive salience of alternative partners". Low self-expansion in a relationship increases interest in alternatives, and the risk of infidelity.

Relativity of reward

Additionally, studies have shown that different individuals can be affected differently by the same potential reward, and that the meaning of a reward can vary with the conditions of its receipt or the specific goals of the individual (e.g. whether it satisfies a present need).

• In an experiment in which subjects were instructed to either cooperate or compete in a word game (in which the partner always won most of a monetary reward), partners were liked better when they followed instructions (either cooperating or competing), rather than when they behaved "inappropriately" and always shared the money. Therefore, it cannot be assumed that altruistic behavior is always viewed positively; it could also be viewed as inappropriate in some situations, even belittling, patronizing or manipulative.
• A study found that subjects who had racial prejudice liked an individual more when the individual evaluated them positively on personality characteristics, even if they had racial bias against the individual, but not as much as they liked an individual whom they did not have racial bias against.
• Two studies found a difference in whether subjects liked a person who gave them a positive evaluation, when they were led to believe they had done poorly on a task. In one study, the subjects were telephone operators who might have known each other, and did not like positive evaluators more than negative evaluators in the situation where they did not share the positive opinion. In the other study, the subjects were strangers who did always like the positive evaluators better, interpreted as being more likely to accept the evaluations at face value.
• A study found that when subjects presented arguments on a contemporary issue, whether they liked an evaluator depended on whether they presented their own position or not. If they presented their own position, liking depended on the evaluator's agreement with the position; if they presented a position opposite to their own, liking primarily depended on whether they agreed on the evaluation of their performance instead.
• A group of studies have shown that individuals who give a positive evaluation are liked better when their positive evaluation is received after a negative evaluation. For example, attraction to an agreeing person is greater after disagreement by others than after agreement, interpreted as drive reducing, wherein disagreement is arousing and subsequent agreement reduces this drive state.
• Which personality characteristics are liked has been found to depend on an individual's own personality and culture.

Readiness

A "readiness" to enter a relationship is identified as an antecedent to falling in love, originally emphasized by the psychoanalyst Theodor Reik. Readiness is also likened to the idea of being "in love with love". The process of falling in love can be seen as an interplay between both this readiness (on the one hand), and a potential partner's appeal (on the other hand). Sometimes readiness can be so intense that a person falls in love with somebody who only has a minimal appeal. With lower readiness, the specific set of partner characteristics becomes more important.

Reik believed that unhappy people tend to be the most vulnerable to love, elaborating on a claim by Sigmund Freud that "happy people never make fantasies, only unsatisfied ones do". Elaine Hatfield concurs, saying "the greater our need, the more grandiose our fantasies".

An experiment by Hatfield found that college women whose self-esteem was lowered by negative feedback liked a man who asked them out on a date more than those women whose self-esteem was raised by positive feedback. The finding has been related as fitting a drive-reduction interpretation of reinforcement, that is, liking was greater for those that needed the ego boost of a potentially positive experience. Another important factor to readiness is loneliness. Phillip Shaver & Cindy Hazan argued that if people have many unmet social needs and are unaware, then a sign somebody is interested in them may become magnified into something quite unrealistic.

Readiness is described as heightening one's susceptibility to limerence—the kind of passionate love (or "all-absorbing" infatuated love) which is commonly unrequited, and felt for somebody unreachable.

Fantasy

See also: Biology of romantic love § Positive illusions, and Limerence § Crystallization

Interpersonal attraction researchers generally assumed liking is based on the actual rewards from interpersonal contact; however, Ellen Berscheid & Elaine Hatfield have also written that it seems doubtful that people are so "reality-bound". They suggest the potential future rewards one fantasizes about are an important consideration in the generation of passionate & romantic love:

When the lover closes his eyes and daydreams, he can summon up a flawless partner—a partner who instantaneously satisfies all his unspoken, conflicting, and fleeting desires. In fantasy he may receive unlimited reward or he may anticipate that he would receive unlimited reward were he ever to actually meet his ideal. Compared to our grandiose fantasies, the level of reward we receive in our real interactions is severely circumscribed. As a consequence, sometimes the most extreme passion is aroused by partners who exist only in imagination or partners who are barely known.

Dorothy Tennov believed that passionate fantasy must seem at least somewhat plausible, however unrealistic. When contact with a loved one is only limited, people can also tend to only notice the good things. With more routine contact, they could notice the things they don't like and become bored.

Reinforcement

The mechanics of interpersonal attraction are believed to follow principles of reinforcement and classical conditioning.

"Reinforcement" is the strengthening of learning in some way; several different paradigms are distinguished:

• Positive reinforcement (reward) increases the frequency of a response leading to a desired stimulus.
• Negative reinforcement also increases the frequency of a response, but with an aversive stimulus which must be removed or avoided.
• Punishment (different from negative reinforcement) is a painful or unwanted stimulus that decreases the frequency of a response leading to the encounter.

Classical (or Pavlovian) conditioning is essentially learning by association: when two things happen together, we come to associate them and expect them together. Ivan Pavlov, who developed the theory, is said to have trained dogs to salivate (having an automatic reflex response) at the sound of a bell by repeatedly ringing it when food was delivered. In this paradigm, a "neutral stimulus" is paired along with a biological stimulus (an "unconditioned stimulus") which elicits a usually innate reflex response (an "unconditioned response") so that when the previously neutral stimulus (now a "conditioned stimulus") is presented again by itself it elicits a new reflex response (a "conditioned response").

Law of attraction

As revised by Byrne and Rhamey (1965), the law states that

${\displaystyle Y=m\left[\frac{\sum (PR\times M)}{\sum (PR\times M)+\sum (NR\times M^{\prime })}\right]+k}$

(where Y is the attraction, M and M′ are magnitudes and m and k are the slope and Y intercept, respectively), or that attraction toward a person is a positive linear function of the sum of the weighted positive reinforcements (Number × Magnitude) associated with him, divided by the total number of weighted positive and negative reinforcements associated with him.

Gerald Clore & Donn Byrne (1974)

In Pavlovian theory, reinforcement is described as this repeated pairing of an unconditioned (or unlearned) stimulus along with a conditioned (or learned) one, which strengthens the association, until eventually the conditioned stimulus elicits the response on its own. According to a similar mechanic, liking for a person results when an individual experiences reward in the presence of that person, although regardless of the actual relationship between the person and the rewarding event. The liked person then becomes a secondary reinforcer, meaning if their presence is contingent on a particular behavior, that behavior should be strengthened.

The "reinforcement-affect model", developed by Donn Byrne & Gerald Clore, additionally posits that attraction is based on the positive affect which accompanies reinforcement, and that these feelings spread from one stimulus to another via association:

(a) a variety of social communications and other interpersonal events can be classed as either reinforcing or punishing; (b) reinforcing events elicit positive affect, while punishing events generate negative affect; (c) stimuli associated with positive or negative affect develop the capacity to evoke that affect; and (d) stimuli that evoke positive affect are liked, while stimuli that evoke negative affect are disliked. Thus, one likes others who reward him because they are associated with one's own good feelings.

The authors also acknowledge a complexity in how this reinforcement functions in everyday situations: "Many of the associations made in the process of attraction development are between words, thoughts, images, or collections, rather than between buzzers, electric shocks, or visceral responses."

Liking by association

A variety of studies have been done which support the idea that people who are associated with reinforcement tend to be liked (via classical conditioning), even when they are not the source of reinforcement.

• An experiment by Pawel Lewicki tested this by giving participants a choice between two pictured women, asking them which looked friendlier, and the regular outcome was nearly 50-50. However, when the participants had a friendly interaction beforehand with an experimenter who merely looked similar to a woman pictured, the similar-looking woman was chosen with a 6-to-1 margin. When the interaction was unfriendly, the similar-looking woman was nearly always avoided.
• Another experiment found that college students liked a stranger better when evaluating them in a pleasant room as compared to a hot room.
• Experiments on children found that students liked their classmates better when a teacher responded positively to other students (regardless if they had any instrumental connection to the teacher's positive or negative treatment), and children who merely helped another child with a series of Bingo games liked other children present, even though they had personally won nothing.

Neuroscience

Dopamine is produced in the ventral tegmental area (VTA) of the brain, and projected to the nucleus accumbens (NAc). Dopamine activity in the NAc is key to the attribution of salience.

Further information: Biology of romantic love § Mechanics

"Wanting" versus "liking"

In modern neuroscience, a new distinction is made between "wanting" and "liking", which are dissociable features of rewards.

• "Wanting" refers to incentive salience, the feature by which cues in an environment become attention-grabbing and attractive, like a "motivational magnet", pulling a person towards a reward. Incentive salience is mediated by dopamine activity in the mesolimbic pathway of the brain, originating in the ventral tegmental area. This form of "wanting" is usually marked in quotes, distinguishing it from other (more cognitive) forms of desire involving declarative goals or explicit expectations of future outcomes.
• "Liking" refers to the pleasurable (or hedonic) aspect of rewards which are consummatory, tied to activity in hedonic hotspots of the brain.

Research by Helen Fisher and Arthur Aron has now used "attraction" to refer to romantic love, which involves the experience of incentive salience (or "wanting") for a loved one. Romantic love is conceived of as a motivation or drive (a "desire for union with another") which elicits different emotions depending on the situation, rather than being an emotion itself. Fisher's taxonomical theory, independent emotion systems, groups a litany of related concepts together (e.g. "being in love", romantic love, passionate love, obsessive love, infatuation, and limerence) under one label of a mammalian "attraction system"—theorized to have evolved for focusing attention on a preferred mating partner.^[66][69][70]

The pleasurable (or "liking") aspect of social interactions and romantic love is believed to be related to endogenous opioids, released in hedonic hotspots, according to a long-running theory called the brain opioid theory of social attachment. "Strong liking" for an intimate partner is called companionate love.

The intense, passionate early stage of romantic love is being compared to a behavioral addiction (addiction to a non-substance) where the "substance" is the loved one, because of similar features like craving and obsessionality. In addiction research, the difference between "wanting" and "liking" is used to explain how an addict can compulsively engage in drug-seeking behaviors, despite when taking the drug no longer results in a high or the addiction becomes detrimental to their life. They can also irrationally "want" (i.e. feel compelled towards, in the sense of incentive salience) something which they do not cognitively wish for.

In a way comparable to addiction, people who are in love may "want" a loved person even when interactions with them are not pleasurable. For example, they may want to contact an ex-partner after a rejection, even when that experience will only be painful. It is also possible for a person to be "in love" with somebody they do not like, or who treats them poorly.

Partner addiction hypothesis

Romantic love has been compared to cocaine and opioid addiction.

 

See also: Love addiction

Falling in love is believed to follow mechanics similar to addiction, although not identically. One of the major differences is that the trajectories diverge, with the addictive aspects of romantic love tending to disappear over time in an intimate relationship.

By comparison, in a drug addiction, the detrimental aspects magnify with repeated drug use, turning into compulsions, a loss of control and a negative emotional state. It has been speculated that the difference could be related to oxytocin activity—present in romantic love, but not in addiction. Oxytocin seems to ameliorate the effects of drug withdrawal, and it might inhibit the more long-term, excessive effects of addiction. Oxytocin interactions would be more present in reciprocated love, so the comparative lack thereof would also explain some of the more maladaptive features of infatuation (social anxiety, sleep difficulties, etc.) present in cases of fast-arising or unrequited love.

A number of theories have been proposed for how addictions begin and perpetuate. A theory by Wolfram Schultz states that rather than encoding reward per se, dopamine encodes a "reward prediction error" (RPE): the difference between the predicted value of a reward, and the actual value upon receiving it (i.e. whether it was better than, equal to, or worse than expected). In this theory, RPE is part of a mechanism for reinforcement learning, which associates rewards with the cues which predicted them. An example of a reward-predicting cue is a lever used in an experiment, which opens a box with food (the reward). Rewards have to be surprising or unexpected for learning to occur, because (in other words) if there is no error then a current behavior can be maintained and will not change. An fMRI study found that people in relationships experienced brain activity in reward areas consistent with RPE, in response to having expectations about their partners' appraisal of them either validated or violated.

Drugs of abuse (like cocaine) artificially overstimulating dopamine neurons, thus hijacking the mechanism by mimicking an RPE signal which is much stronger than could be produced naturally.

In the theory of "incentive sensitization" developed by Kent Berridge & Terry Robinson, repeated drug use renders the brain hypersensitive to drugs and drug cues, resulting in pathological levels of "wanting" to use drugs. The attribution of incentive salience "wanting" (what is attention-grabbing) follows a Pavlovian learning paradigm (i.e. classical conditioning). While "wanting" can apply innately to some unconditioned stimuli, it can also become attributed to a conditioned stimulus by pairing it with the receipt of a natural (innate) reward, thereby attributing incentive salience by Pavlovian association. When a conditioned stimulus is attributed incentive salience, it becomes a reinforcer too, being attractive and guiding motivated behavior towards reward, once encountered again. This cue-triggered "wanting" (by a conditioned stimulus) can even be so powerful that crack cocaine addicts sometimes "chase ghosts", scrambling for white granules they know aren't cocaine. For a person in love, reminder cues such as letters or photographs can also induce craving.

In the nascent phases of both addiction and attachment, when interactions with the desired object produce rewarding outcomes, dopamine is released in the nucleus accumbens shell which increases the salience of cues predicting the reward. In a "partner addiction" (unlike drugs of abuse), the sensory information being gathered is mostly social, for example, looks, touches, words, scents, body shape and face, or sexual experiences. Salience in response to social stimuli is believed to be modulated by oxytocin, which is projected to reward areas.

These different neurochemical systems interact, as a cooperation between dopamine (incentive salience), opioids (positive rewards) and oxytocin (enhancement from social cues). A positive feedback loop is created, where behavior and predictive cues then become positively reinforced, accumulating positive associations over time.

Withdrawal

In drug addiction, a shift occurs, first starting with positive reinforcement (of binging and intoxication) in the earlier stages, but then transitioning over time towards negative reinforcement (of avoiding withdrawal). The aversive stress-like effects of this later stage recruit the dynorphin and corticotropin release factor (CRF) systems in the brain. Dynorphin promotes negative affect; CRF causes withdrawal-induced anxiety and craving.

This stress causes CRF to release into the ventral tegmental area and nucleus accumbens shell, motivating the reinstatement of drug use. A similar effect is hypothesized in pair bonds, where stress after separation or social loss motivates a person to return to a partner; however, experiments have not investigated this in humans, only rodents.

Reinforcement schedules

Infatuated love essentially thrives under intermittent reinforcement—also the mechanic a slot machine relies on.

A reinforcement schedule determines when and how often a given behavior is reinforced. Each type of schedule is associated with a different characteristic response. Liking and passionate love are believed to operate primarily under different reinforcement schedules.

If every single response is reinforced, the schedule is called continuous reinforcement (or a fixed ratio of 1). Otherwise, if only some responses are reinforced, then the schedule is called partial or intermittent reinforcement. Schedules affect the rate of learning, as well as how resistant the learned response is to extinction (where the response is weakened or inhibited) after reinforcement is discontinued. With variable-interval and variable-ratio schedules, the resistance to extinction is very high; extinction only occurs very slowly compared to other schedules.

Common reinforcement schedules

Schedule	Example
Continuous	Every response is reinforced
Fixed ratio	Being paid monthly
Fixed interval	Being paid commission, where extra money is made with extra work
Variable interval	Being paid on an irregular interval, as a self-employed person would be
Variable ratio	Gambling

Liking seems to operate primarily under fixed-ratio and fixed-interval schedules, when an individual is fed a more or less "steady diet" of reinforcement.

By comparison, passionate love (infatuation or limerence) operates primarily under variable-ratio and variable-interval schedules. Passionate love is said to essentially thrive under intermittent reinforcement, in situations with only irregular meetings between lovers, or with ambiguous and changing perceptions over whether one's love is returned. Uncertainty seems to magnify cue-triggered incentive salience "wanting". A comparable type of situation is that of a slot machine, where the rewards are designed to be always unpredictable so the gambler cannot understand the pattern. Unable to habituate to the experience, for some people the exhilarating high from the unexpected wins leads to gambling addiction and compulsions. If the machine paid out on a regular interval (so that the rewards were expected), it would not be as exciting.

The phenomenon of "traumatic bonding" in abusive relationships is also believed to rely on intermittent reinforcement, but by alternating good and bad treatment (also called "intermittent maltreatment"). According to Elaine Hatfield, 'Consistency generates little emotion; it is inconsistency that we respond to. If a person always treats us with love and respect, we start to take that person for granted. We like him or her—but "ho hum". Similarly, if a person is always cold and rejecting, we eventually tend to disregard his or her criticisms. [...] What would generate a spark of interest, however, is if our admiring friend suddenly started treating us with contempt—or if our arch enemy started inundating us with kindness.'

Attachment style

Uncertain reciprocation has also been interpreted in terms of attachment anxiety. Passionate love has long been compared to anxious attachment (although the states are distinct), because of a parallel between preoccupation features. Anxious attachment is believed to increase one's susceptibility to limerence, and worsen the "symptoms".

"Attachment style" refers to differences in attachment-related thoughts and behaviors, relating to the concept of security vs. insecurity. This is split into components of anxiety (worrying the partner is available, attentive and responsive) and avoidance (preference not to rely on others or open up emotionally). Attachment style is considered as an individual difference, but may also be relationship-specific, for example, an avoidant partner can make a normally secure person feel and act anxious (as in the person–situation debate). The formation of attachment style is complicated, starting in childhood and adolescence, but also having a heritable component.

It has been argued that attachment style develops based on the consistency of support given by an attachment figure (e.g. parent or partner), becoming either secure (from responsive support), avoidant (from unresponsive support) or anxious (from inconsistent support). A study investigated the effect of reinforcement schedules on the formation of relationship-specific attachment styles. This study used a negative reinforcement scheme where participants were under threat of an electric shock, which required the help of a supporter (whom they did not know) to prevent. The availability to call a supporter to stop the electric shock was either continuous or variable-ratio, and this variable-ratio support was found to increase approach-related attentional bias towards the supporter (measured with EEG) more than continuous support. It is argued that a negative reinforcement learning process underlies the formation of attachment styles, and that this kind of unpredictability enhances the incentive salience of receiving support, but while also producing an ambivalent dispositional attitude. However, it is cautioned that real-world attachment processes play out in contexts which are different from the experiment—for example, a hug after a bad day.

Under the attachment view, passion wanes as a relationship becomes more secure over time (i.e. as uncertainty is reduced).

Duration of romantic love

Using intermittent communication to string somebody along without a commitment is called "breadcrumbing".

Desire fades because of a habituation effect on dopamine activity: as a reward is more easily and predictably obtained, the dopamine release in response to reward cues decreases. Usually romantic love inside a relationship lasts for just about a year or 18 months. Still, in some cases passionate "romantic ferver" can last much longer, even a lifetime. The love researcher Helen Fisher has spoken about her "living apart together" arrangement with her husband (living separately two days a week), saying it's a "great way to have a really long-term romance". In a 2024 podcast, she recalled being "madly in love" with him for nine years.

Brain scans using fMRI of people who say they're still "madly in love" in long-term relationships found activations in dopamine-rich reward areas ("wanting"), but also in an area rich with opiate receptors ("liking"). Unlike people who were newly in love, the participants also did not show activity in areas associated with anxiety and fear, and reported less of the obsessional features (intrusive thinking, uncertainty and mood swings) which are a characteristic of infatuation or limerence.

Limerence can be unending when it's unrequited, for example, in the case of receiving mixed signals, making it difficult to extinguish. Once a relationship occurs, extinction can take place.