GABAA receptor

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/GABAA_receptor

Structure of the GAB_AA receptor (α1β1γ2S: PDB: 6DW1). Top: side view of the GABA_A receptor embedded in a cell membrane. Bottom: view of the receptor from the extracellular face of the membrane. The subunits are labeled according to the GABA_A nomenclature and the approximate locations of the GABA and benzodiazepine (BZ) binding sites are noted (between the α- and β-subunits and between the α- and γ-subunits respectively).

Schematic structure of the GABA_A receptor. Left: GABA_A monomeric subunit embedded in a lipid bilayer (yellow lines connected to blue spheres). The four transmembrane α-helices (1–4) are depicted as cylinders. The disulfide bond in the N-terminal extracellular domain which is characteristic of the family of cys-loop receptors (which includes the GABA_A receptor) is depicted as a yellow line. Right: Five subunits symmetrically arranged about the central chloride anion conduction pore. The extracellular loops are not depicted for the sake of clarity.

The GABA_A receptor (GABA_AR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABA_A receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl⁻
) and, to a lesser extent, bicarbonate ions (HCO⁻
₃).

GABA_AR are members of the ligand-gated ion channel receptor superfamily, which is a chloride channel family with a dozen or more heterotetrametric subtypes and 19 distinct subunits. These subtypes have distinct brain regional and subcellular localization, age-dependent expression, and the ability to undergo plastic alterations in response to experience, including drug exposure.

GABA_AR is not just the target of agonist depressants and antagonist convulsants, but most GABA_AR medicines also act at additional (allosteric) binding sites on GABA_AR proteins. Some sedatives and anxiolytics, such as benzodiazepines and related medicines, act on GABA_AR subtype-dependent extracellular domain sites. Alcohols and neurosteroids, among other general anesthetics, act at GABA_AR subunit-interface transmembrane locations. High anesthetic dosages of ethanol act on GABA_AR subtype-dependent transmembrane domain locations. Ethanol acts at GABA_AR subtype-dependent extracellular domain locations at low intoxication concentrations. Thus, GABA_AR subtypes have pharmacologically distinct receptor binding sites for a diverse range of therapeutically significant neuropharmacological drugs.

Depending on the membrane potential and the ionic concentration difference, this can result in ionic fluxes across the pore. If the membrane potential is higher than the equilibrium potential (also known as the reversal potential) for chloride ions, when the receptor is activated Cl⁻
will flow into the cell. This causes an inhibitory effect on neurotransmission by diminishing the chance of a successful action potential occurring at the postsynaptic cell. The reversal potential of the GABA_A-mediated inhibitory postsynaptic potential (IPSP) in normal solution is −70 mV, contrasting the GABA_B IPSP (−100 mV).

The active site of the GABA_A receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline. The protein also contains a number of different allosteric binding sites which modulate the activity of the receptor indirectly. These allosteric sites are the targets of various other drugs, including the benzodiazepines, nonbenzodiazepines, neuroactive steroids, barbiturates, alcohol (ethanol), inhaled anaesthetics, kavalactones, cicutoxin, and picrotoxin, among others.

Much like the GABA_A receptor, the GABA_B receptor is an obligatory heterodimer consisting of GABA_B1 and GABA_B2 subunits. These subunits include an extracellular Venus Flytrap domain (VFT) and a transmembrane domain containing seven α-helices (7TM domain). These structural components play a vital role in intricately modulating neurotransmission and interactions with drugs. 

Target for benzodiazepines

The ionotropic GABA_A receptor protein complex is also the molecular target of the benzodiazepine class of tranquilizer drugs. Benzodiazepines do not bind to the same receptor site on the protein complex as does the endogenous ligand GABA (whose binding site is located between α- and β-subunits), but bind to distinct benzodiazepine binding sites situated at the interface between the α- and γ-subunits of α- and γ-subunit containing GABA_A receptors. While the majority of GABA_A receptors (those containing α1-, α2-, α3-, or α5-subunits) are benzodiazepine sensitive, there exists a minority of GABA_A receptors (α4- or α6-subunit containing) which are insensitive to classical 1,4-benzodiazepines, but instead are sensitive to other classes of GABAergic drugs such as neurosteroids and alcohol. In addition peripheral benzodiazepine receptors exist which are not associated with GABA_A receptors. As a result, the IUPHAR has recommended that the terms "BZ receptor", "GABA/BZ receptor" and "omega receptor" no longer be used and that the term "benzodiazepine receptor" be replaced with "benzodiazepine site". Benzodiazepines like diazepam and midazolam act as positive allosteric modulators for GABA_A receptors. When these receptors are activated, there's a rise in intracellular chloride levels, resulting in cell membrane hyperpolarization and decreased excitation.

In order for GABA_A receptors to be sensitive to the action of benzodiazepines they need to contain an α and a γ subunit, between which the benzodiazepine binds. Once bound, the benzodiazepine locks the GABA_A receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABA_A receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarising the membrane. This potentiates the inhibitory effect of the available GABA leading to sedative and anxiolytic effects.

Different benzodiazepines have different affinities for GABA_A receptors made up of different collection of subunits, and this means that their pharmacological profile varies with subtype selectivity. For instance, benzodiazepine receptor ligands with high activity at the α1 and/or α5 tend to be more associated with sedation, ataxia and amnesia, whereas those with higher activity at GABA_A receptors containing α2 and/or α3 subunits generally have greater anxiolytic activity. Anticonvulsant effects can be produced by agonists acting at any of the GABA_A subtypes, but current research in this area is focused mainly on producing α₂-selective agonists as anticonvulsants which lack the side effects of older drugs such as sedation and amnesia.

The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABA_A receptor, and also produces different effects on binding, with the benzodiazepines increasing the frequency of the chloride channel opening, while barbiturates increase the duration of chloride channel opening when GABA is bound. Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled.

Also note that some GABA_A agonists such as muscimol and gaboxadol do bind to the same site on the GABA_A receptor complex as GABA itself, and consequently produce effects which are similar but not identical to those of positive allosteric modulators like benzodiazepines.

Structure and function

Schematic diagram of a GABA_A receptor protein ((α1)₂(β2)₂(γ2)) which illustrates the five combined subunits that form the protein, the chloride (Cl⁻
) ion channel pore, the two GABA active binding sites at the α1 and β2 interfaces, and the benzodiazepine (BZD) allosteric binding site

Side view of the EM structure of the α1β3γ2 GABAA receptor. GABA and the anaesthetic etomidate are coloured magenta. Subunits in different colours. One alpha and one beta subunit is hidden. Green chloride ions illustrated in the channel pore.

Structural understanding of the GABA_A receptor was initially based on homology models, obtained using crystal structures of homologous proteins like Acetylcholine binding protein (AChBP) and nicotinic acetylcholine (nACh) receptors as templates. The much sought structure of a GABA_A receptor was finally resolved, with the disclosure of the crystal structure of human β3 homopentameric GABA_A receptor. Whilst this was a major development, the majority of GABA_A receptors are heteromeric and the structure did not provide any details of the benzodiazepine binding site. This was finally elucidated in 2018 by the publication of a high resolution cryo-EM structure of rat α1β1γ2S receptor and human α1β2γ2 receptor bound with GABA and the neutral benzodiazepine flumazenil.

GABA_A receptors are pentameric transmembrane receptors which consist of five subunits arranged around a central pore. Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. The receptor sits in the membrane of its neuron, usually localized at a synapse, postsynaptically. However, some isoforms may be found extrasynaptically. When vesicles of GABA are released presynaptically and activate the GABA receptors at the synapse, this is known as phasic inhibition. However, the GABA escaping from the synaptic cleft can activate receptors on presynaptic terminals or at neighbouring synapses on the same or adjacent neurons (a phenomenon termed 'spillover') in addition to the constant, low GABA concentrations in the extracellular space results in persistent activation of the GABA_A receptors known as tonic inhibition.

The ligand GABA is the endogenous compound that causes this receptor to open; once bound to GABA, the protein receptor changes conformation within the membrane, opening the pore in order to allow chloride anions (Cl⁻
) and, to a lesser extent, bicarbonate ions (HCO⁻
₃) to pass down their electrochemical gradient. The binding site to GABA is about 80Å away from the narrowest part of the ion channel. Recent computational studies have suggested an allosteric mechanism whereby GABA binding leads to ion channel opening. Because the reversal potential for chloride in most mature neurons is close to or more negative than the resting membrane potential, activation of GABA_A receptors tends to stabilize or hyperpolarise the resting potential, and can make it more difficult for excitatory neurotransmitters to depolarize the neuron and generate an action potential. The net effect therefore typically inhibitory, reducing the activity of the neuron, although depolarizing currents have been observed in response to GABA in immature neurons in early development. This effect during development is due to a modified Cl⁻
gradient wherein the anions leave the cells through the GABA_A receptors, since their intracellular chlorine concentration is higher than the extracellular. The difference in extracellular chlorine anion concentration is presumed to be due to the higher activity of chloride transporters, such as NKCC1, transporting chloride into cells which are present early in development, whereas, for instance, KCC2 transports chloride out of cells and is the dominant factor in establishing the chloride gradient later in development. These depolarization events have shown to be key in neuronal development. In the mature neuron, the GABA_A channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP). The endogenous ligand that binds to the benzodiazepine site is inosine.

Proper developmental, neuronal cell-type-specific, and activity-dependent GABAergic transmission control is required for nearly all aspects of CNS function.

It has been proposed that the GABAergic system is disrupted in numerous neurodevelopmental diseases, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and that it is a crucial potential target for therapeutic intervention.

Subunits

GABA_A receptors are members of the large pentameric ligand gated ion channel (previously referred to as "Cys-loop" receptors) super-family of evolutionarily related and structurally similar ligand-gated ion channels that also includes nicotinic acetylcholine receptors, glycine receptors, and the 5HT₃ receptor. There are numerous subunit isoforms for the GABA_A receptor, which determine the receptor's agonist affinity, chance of opening, conductance, and other properties.

In humans, the units are as follows:

• six types of α subunits (GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6)
• three βs (GABRB1, GABRB2, GABRB3)
• three γs (GABRG1, GABRG2, GABRG3)
• as well as a δ (GABRD), an ε (GABRE), a π (GABRP), and a θ (GABRQ)

There are three ρ units (GABRR1, GABRR2, GABRR3); however, these do not coassemble with the classical GABA_A units listed above, but rather homooligomerize to form GABA_A-ρ receptors (formerly classified as GABA_C receptors but now this nomenclature has been deprecated).

Combinatorial arrays

Given the large number of GABA_A receptors, a great diversity of final pentameric receptor subtypes is possible. Methods to produce cell-based laboratory access to a greater number of possible GABA_A receptor subunit combinations allow teasing apart of the contribution of specific receptor subtypes and their physiological and pathophysiological function and role in the CNS and in disease.

Distribution

GABA_A receptors are responsible for most of the physiological activities of GABA in the central nervous system, and the receptor subtypes vary significantly. Subunit composition can vary widely between regions and subtypes may be associated with specific functions. The minimal requirement to produce a GABA-gated ion channel is the inclusion of an α and a β subunit. The most common GABA_A receptor is a pentamer comprising two α's, two β's, and a γ (α₂β₂γ). In neurons themselves, the type of GABA_A receptor subunits and their densities can vary between cell bodies and dendrites. Benzodiazepines and barbiturates amplify the inhibitory effects mediated by the GABAA receptor. GABA_A receptors can also be found in other tissues, including leydig cells, placenta, immune cells, liver, bone growth plates and several other endocrine tissues. Subunit expression varies between 'normal' tissue and malignancies, as GABA_A receptors can influence cell proliferation.

Distribution of Receptor Types

Isoform	Synaptic/Extrasynaptic	Anatomical location
α1β3γ2S	Both	Widespread
α2β3γ2S	Both	Widespread
α3β3γ2S	Both	Reticular thalamic nucleus
α4β3γ2S	Both	Thalamic relay cells
α5β3γ2S	Both	Hippocampal pyramidal cells
α6β3γ2S	Both	Cerebellar granule cells
α1β2γ2S	Both	Widespread, most abundant
α4β3δ	Extrasynaptic	Thalamic relay cells
α6β3δ	Extrasynaptic	Cerebellar granule cells
α1β2	Extrasynaptic	Widespread
α1β3	Extrasynaptic	Thalamus, hypothalamus
α1β2δ	Extrasynaptic	Hippocampus
α4β2δ	Extrasynaptic	Hippocampus, Prefrontal cortex
α3β3θ	Extrasynaptic	Hypothalamus
α3β3ε	Extrasynaptic	Hypothalamus

Ligands

GABA_A receptor and where various ligands bind.

A number of ligands have been found to bind to various sites on the GABA_A receptor complex and modulate it besides GABA itself. A ligand can possess one or more properties of the following types. Unfortunately the literature often does not distinguish these types properly.

Types

GABA bound at its orthosteric site in the beta-alpha interface of an α1β2γ2 GABAA receptor. H-atoms hidden.

• Orthosteric agonists and antagonists: bind to the main receptor site (the site where GABA normally binds, also referred to as the "active" or "orthosteric" site). Agonists activate the receptor, resulting in increased Cl⁻
  conductance. Antagonists, though they have no effect on their own, compete with GABA for binding and thereby inhibit its action, resulting in decreased Cl⁻
  conductance.
• First order allosteric modulators: bind to allosteric sites on the receptor complex and affect it either in a positive (PAM), negative (NAM) or neutral/silent (SAM) manner, causing increased or decreased efficiency of the main site and therefore an indirect increase or decrease in Cl⁻
  conductance. SAMs do not affect the conductance, but occupy the binding site.
• Second order modulators: bind to an allosteric site on the receptor complex and modulate the effect of first order modulators.
• Open channel blockers: prolong ligand-receptor occupancy, activation kinetics and Cl ion flux in a subunit configuration-dependent and sensitization-state dependent manner.
• Non-competitive channel blockers: bind to or near the central pore of the receptor complex and directly block Cl⁻
  conductance through the ion channel.

Examples

• Orthosteric agonists: GABA, gaboxadol, isoguvacine, muscimol, progabide, beta-alanine, taurine, piperidine-4-sulfonic acid (partial agonist).
• Orthosteric antagonists: bicuculline, gabazine.
• Positive allosteric modulators: abecarnil, azocarnil (photoswitchable), barbiturates, benzodiazepines, certain carbamates (e.g., carisoprodol, meprobamate, lorbamate), honokiol, magnolol, baicalin, baicelin, thienodiazepines, alcohol (ethanol), etomidate, glutethimide, kavalactones, meprobamate, quinazolinones (e.g., methaqualone, etaqualone, diproqualone), neuroactive steroids, niacin/niacinamide, nonbenzodiazepines (e.g., zolpidem, eszopiclone), propofol, stiripentol, theanine, valerenic acid, volatile/inhaled anesthetics, lanthanum, riluzole, and menthol.
• Negative allosteric modulators: flumazenil, Ro15-4513, sarmazenil, pregnenolone sulfate, amentoflavone, and zinc.
• Inverse allosteric agonists: beta-carbolines (e.g., harmine, harmaline, tetrahydroharmine).
• Second-order modulators: (−)‐epigallocatechin‐3‐gallate.
• Non-competitive channel blockers: cicutoxin, oenanthotoxin, pentylenetetrazol, picrotoxin, thujone, and lindane.

Effects

Ligands which contribute to receptor activation typically have anxiolytic, anticonvulsant, amnesic, sedative, hypnotic, euphoriant, and muscle relaxant properties. Some such as muscimol and the z-drugs may also be hallucinogenic. Ligands which decrease receptor activation usually have opposite effects, including anxiogenesis and convulsion. Some of the subtype-selective negative allosteric modulators such as α₅IA are being investigated for their nootropic effects, as well as treatments for the unwanted side effects of other GABAergic drugs. Advances in molecular pharmacology and genetic manipulation of rat genes have revealed that distinct subtypes of the GABA_A receptor mediate certain parts of the anaesthetic behavioral repertoire.

Novel drugs

A useful property of the many benzodiazepine site allosteric modulators is that they may display selective binding to particular subsets of receptors comprising specific subunits. This allows one to determine which GABA_A receptor subunit combinations are prevalent in particular brain areas and provides a clue as to which subunit combinations may be responsible for behavioral effects of drugs acting at GABA_A receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic effects from undesirable side effects. Few subtype selective ligands have gone into clinical use as yet, with the exception of zolpidem which is reasonably selective for α₁, but several more selective compounds are in development such as the α₃-selective drug adipiplon. There are many examples of subtype-selective compounds which are widely used in scientific research, including:

Diazepam is a benzodiazepine medication that is FDA approved for the treatment of anxiety disorders, the short-term relief of anxiety symptoms, spasticity associated with upper motor neuron disorders, adjunct therapy for muscle spasms, preoperative anxiety relief, the management of certain refractory epileptic patients, and as an adjunct in severe recurrent convulsive seizures and status epilepticus.

• CL-218,872 (highly α₁-selective agonist)
• bretazenil (subtype-selective partial agonist)
• imidazenil and L-838,417 (both partial agonists at some subtypes, but weak antagonists at others)
• QH-ii-066 (full agonist highly selective for α₅ subtype)
• α₅IA (selective inverse agonist for α₅ subtype)
• SL-651,498 (full agonist at α₂ and α₃ subtypes, and as a partial agonist at α₁ and α₅
• 3-acyl-4-quinolones: selective for α₁ over α₃

Paradoxical reactions

There are multiple indications that paradoxical reactions upon — for example — benzodiazepines, barbiturates, inhalational anesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABA_A receptors. The combination of the five subunits of the receptor (see images above) can be altered in such a way that for example the receptor's response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.

There are estimates that about 2–3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.

Argument from poor design

From Wikipedia, the free encyclopedia

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

 

The argument from poor design, also known as the dysteleological argument, is an argument against the assumption of the existence of a creator God, based on the reasoning that any omnipotent and omnibenevolent deity or deities would not create organisms with the perceived suboptimal designs that occur in nature.

The argument is structured as a basic modus ponens: if "creation" contains many defects, then design appears an implausible theory for the origin of earthly existence. Proponents most commonly use the argument in a weaker way, however: not with the aim of disproving the existence of God, but rather as a reductio ad absurdum of the well-known argument from design (which suggests that living things appear too well-designed to have originated by chance, and so an intelligent God or gods must have deliberately created them).

Although the phrase "argument from poor design" has seen little use, this type of argument has been advanced many times using words and phrases such as "poor design", "suboptimal design", "unintelligent design" or "dysteleology/dysteleological". The nineteenth-century biologist Ernst Haeckel applied the term "dysteleology" to the implications of organs so rudimentary as to be useless to the life of an organism. In his 1868 book Natürliche Schöpfungsgeschichte (The History of Creation), Haeckel devoted most of a chapter to the argument, ending with the proposition (perhaps with tongue slightly in cheek) of "a theory of the unsuitability of parts in organisms, as a counter-hypothesis to the old popular doctrine of the suitability of parts". In 2005, Donald Wise of the University of Massachusetts Amherst popularised the term "incompetent design" (a play on "intelligent design"), to describe aspects of nature seen as flawed in design.

Traditional Christian theological responses generally posit that God constructed a perfect universe but that humanity's misuse of its free will to rebel against God has resulted in the corruption of divine good design.

Overview

Natural selection is expected to push fitness to a peak, but that peak often is not the highest.

The argument runs that:

1. An omnipotent, omniscient, omnibenevolent creator God would create organisms that have optimal design.
2. Organisms have features that are suboptimal.
3. Therefore, God either did not create these organisms or is not omnipotent, omniscient and omnibenevolent.

It is sometimes used as a reductio ad absurdum of the well-known argument from design, which runs as follows:

1. Living things are too well-designed to have originated by chance.
2. Therefore, life must have been created by an intelligent creator.
3. This creator is God.

"Poor design" is consistent with the predictions of the scientific theory of evolution by means of natural selection. This predicts that features that were evolved for certain uses are then reused or co-opted for different uses, or abandoned altogether; and that suboptimal state is due to the inability of the hereditary mechanism to eliminate the particular vestiges of the evolutionary process.

In fitness landscape terms, natural selection will always push "up the hill", but a species cannot normally get from a lower peak to a higher peak without first going through a valley.

The argument from poor design is one of the arguments that was used by Charles Darwin; modern proponents have included Stephen Jay Gould, Richard Dawkins, and Nathan H. Lents. They argue that such features can be explained as a consequence of the gradual, cumulative nature of the evolutionary process. Theistic evolutionists generally reject the argument from design, but do still maintain belief in the existence of God.

Examples

In humans

Fatal flaws

Artist's representation of an ectopic pregnancy. Critics cite such common biological occurrences as contradictory to the 'watchmaker analogy'.

American scientist Nathan H. Lents published his book on poor design in the human body and genome in 2018 titled Human Errors. The book ignited a firestorm of criticism from the creationist community but was well received by the scientific community and received unanimously favorable reviews in the dozens of non-creationist media outlets that covered it.

Several defects in human anatomy can result in death, especially without modern medical care:

• In the human female, a fertilized egg can implant into the fallopian tube, cervix or ovary rather than the uterus causing an ectopic pregnancy. The existence of a cavity between the ovary and the fallopian tube could indicate a flawed design in the female reproductive system. Prior to modern surgery, ectopic pregnancy invariably caused the deaths of both mother and baby. Even in modern times, in almost all cases the pregnancy must be aborted to save the life of the mother.
• In the human female, the birth canal passes through the pelvis. The prenatal skull will deform to a surprising extent. However, if the baby's head is significantly larger than the pelvic opening, the baby cannot be born naturally. Prior to the development of modern surgery (caesarean section), such a complication would lead to the death of the mother, the baby, or both. Other birthing complications such as breech birth are worsened by this position of the birth canal.
• In the human male, testes develop initially within the abdomen. Later during gestation, they migrate through the abdominal wall into the scrotum. This causes two weak points in the abdominal wall where hernias can later form. Prior to modern surgical techniques, complications from hernias, such as intestinal blockage and gangrene, usually resulted in death.
• The existence of the pharynx, a passage used for both ingestion and respiration, with the consequent drastic increase in the risk of choking.
• The breathing reflex is stimulated not directly by the absence of oxygen but indirectly by the presence of carbon dioxide. A result is that, at high altitudes, oxygen deprivation can occur in unadapted individuals who do not consciously increase their breathing rate.
• The human appendix is a vestigial organ thought to serve no purpose. Appendicitis, an infection of this organ, is a certain death without medical intervention. "During the past few years, however, several studies have suggested its immunological importance for the development and preservation of the intestinal immune system."
• Tinnitus, a phantom auditory sensation, is a maladaptation resulting from hearing loss most often caused by exposure to loud noise. Tinnitus serves no practical purpose, reduces quality of life, may cause depression, and when severe can lead to suicide.

Other flaws

• Barely used nerves and muscles, such as the plantaris muscle of the foot, that are missing in part of the human population and are routinely harvested as spare parts if needed during operations. Another example is the muscles that move the ears, which some people can learn to control to a degree, but serve no purpose in any case.
• The common malformation of the human spinal column, leading to scoliosis, sciatica and congenital misalignment of the vertebrae. The spinal cord cannot ever properly heal if it is damaged, because neurons have become so specialized that they are no longer able to regrow once they reach their mature state. The spinal cord, if broken, will never repair itself and will result in permanent paralysis.
• Almost all animals and plants synthesize their own vitamin C, but humans cannot because the gene for this enzyme is defective (Pseudogene ΨGULO). Lack of vitamin C results in scurvy and eventually death. The gene is also non-functional in other primates and in guinea pigs, but is functional in most other animals.
• The prevalence of congenital diseases and genetic disorders such as Huntington's disease.
• The male urethra passes directly through the prostate, which can produce urinary difficulties if the prostate becomes swollen.
• Crowded teeth and poor sinus drainage, as human faces are significantly flatter than those of other primates although humans share the same tooth set. This results in a number of problems, most notably with wisdom teeth, which can damage neighboring teeth or cause serious infections of the mouth.
• The structure of human eyes (as well as those of all vertebrates). The retina is 'inside out'. The nerves and blood vessels lie on the surface of the retina instead of behind it as is the case in many invertebrate species. This arrangement forces a number of complex adaptations and gives mammals a blind spot. Having the optic nerve connected to the side of the retina that does not receive the light, as is the case in cephalopods, would avoid these problems. Lents and colleagues have proposed that the tapetum lucidum, the reflective surface behind vertebrate retinas, has evolved to overcome the limitations of the inverted retina, as cephalopods have never evolved this structure. However, an 'inverted' retina actually improves image quality through müller cells by reducing distortion. The effects of the blind spots resulting from the inverted retina are cancelled by binocular vision, as the blind spots in both eyes are oppositely angled. Additionally, as cephalopod eyes lack cone cells and might be able to judge color by bringing specific wavelengths to a focus on the retina, an inverted retina might interfere with this mechanism.
• Humans are attracted to junk food's non-nutritious ingredients, and even wholly non-nutritious psychoactive drugs, and can experience physiological adaptations to prefer them to nutrients.

Other life

• In the African locust, nerve cells start in the abdomen but connect to the wing. This leads to unnecessary use of materials.
• Intricate reproductive devices in orchids, apparently constructed from components commonly having different functions in other flowers.
• The use by pandas of their enlarged radial sesamoid bones in a manner similar to how other creatures use thumbs.
• The existence of unnecessary wings in flightless birds, e.g. ostriches.
• The route of the recurrent laryngeal nerve is such that it travels from the brain to the larynx by looping around the aortic arch. This same configuration holds true for many animals; in the case of the giraffe, this results in about twenty feet of extra nerve.
• The enzyme RuBisCO has been described as a "notoriously inefficient" enzyme, as it is inhibited by oxygen, has a very slow turnover and is not saturated at current levels of carbon dioxide in the atmosphere. The enzyme is inhibited as it is unable to distinguish between carbon dioxide and molecular oxygen, with oxygen acting as a competitive enzyme inhibitor. However, RuBisCO remains the key enzyme in carbon fixation, and plants overcome its poor activity by having massive amounts of it inside their cells, making it the most abundant protein on Earth.
• Sturdy but heavy bones, suited for non-flight, occurring in animals like bats. Or, on the converse: unstable, light, hollow bones, suited for flight, occurring in birds like penguins and ostriches, which cannot fly.
• Various vestigial body parts, like the femur and pelvis in whales (evolution indicates the ancestors of whales lived on land).
• Turritopsis dohrnii and species of the genus Hydra have biological immortality, but most animals do not.
• Many species have strong instincts to behave in response to a certain stimulus. Natural selection can leave animals behaving in detrimental ways when they encounter a supernormal stimulus - like a moth flying into a flame.
• Plants are green and not black, as chlorophyll absorbs green light poorly, even though black plants would absorb more light energy.
• Whales and dolphins breathe air, but live in the water, meaning they must swim to the surface frequently to breathe.
• Albatrosses cannot take off or land properly.

Counterarguments

Specific examples

Intelligent design proponent William Dembski questions the first premise of the argument, claiming that "intelligent design" does not need to be optimal.

While the appendix has been previously credited with very little function, research has shown that it serves an important role in the fetus and young adults. Endocrine cells appear in the appendix of the human fetus at around the 11th week of development, which produce various biogenic amines and peptide hormones, compounds that assist with various biological control (homeostatic) mechanisms. In young adults, the appendix has some immune functions.

Responses to counterarguments

In response to the claim that uses have been found for "junk" DNA, proponents note that the fact that some non-coding DNA has a purpose does not establish that all non-coding DNA has a purpose, and that the human genome does include pseudogenes that are nonfunctional "junk", with others noting that some sections of DNA can be randomized, cut, or added to with no apparent effect on the organism in question. The original study that suggested that the Makorin1-p1 served some purpose has been disputed. However, the original study is still frequently cited in newer studies and articles on pseudogenes previously thought to be nonfunctional.

As an argument regarding God

The argument from poor design is sometimes interpreted, by the argumenter or the listener, as an argument against the existence of God, or against characteristics commonly attributed to a creator deity, such as omnipotence, omniscience, or personality. In a weaker form, it is used as an argument for the incompetence of God. The existence of "poor design" (as well as the perceived prodigious "wastefulness" of the evolutionary process) would seem to imply a "poor" designer, or a "blind" designer, or no designer at all. In Gould's words, "If God had designed a beautiful machine to reflect his wisdom and power, surely he would not have used a collection of parts generally fashioned for other purposes. Orchids are not made by an ideal engineer; they are jury-rigged...."

The apparently suboptimal design of organisms has also been used by proponents of theistic evolution to argue in favour of a creator deity who uses natural selection as a mechanism of his creation. Arguers from poor design regard counter-arguments as a false dilemma, imposing that either a creator deity designed life on earth well or flaws in design indicate the life is not designed. This allows proponents of intelligent design to cherry pick which aspects of life constitute design, leading to the unfalsifiability of the theory. Christian proponents of both intelligent design and creationism may claim that good design indicates the creative intelligence of their God, while poor design indicates corruption of the world as a result of free will that caused the fall of man (for example, in Genesis 3:16 Yahweh says to Eve "I will increase your trouble in pregnancy").

Pineapple Express

From Wikipedia, the free encyclopedia

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

November 2006 satellite image showing clouds from north of Hawaii to Washington, a Pineapple Express configuration

Pineapple Express is a specific recurring atmospheric river both in the waters immediately northeast of the Hawaiian Islands and extending northeast to any location along the Pacific coast of North America. It is a non-technical term and a meteorological phenomenon. It is characterized by a strong and persistent large-scale flow of warm moist air, and the associated heavy precipitation. A Pineapple Express is an example of an atmospheric river, which is a more general term for such relatively narrow corridors of enhanced water vapor transport at mid-latitudes around the world.

Causes and effects

How the Madden–Julian oscillation can induce a Pineapple Express

NASA Geostationary Operational Environmental Satellite called GOES-11, image of the "Pineapple Express" captured at 1800 UTC (1 p.m. EST) on 19 December 2010.

A Pineapple Express is driven by a strong, southern branch of the polar jet stream and is marked by the presence of a surface frontal boundary which is typically either slow or stationary, with waves of low pressure traveling along its length. Each of these low-pressure systems brings enhanced rainfall.

The conditions are often created by the Madden–Julian oscillation, an equatorial rainfall pattern which feeds its moisture into this pattern. They are also present during an El Niño episode.

The combination of moisture-laden air, atmospheric dynamics, and orographic enhancement resulting from the passage of this air over the mountain ranges of the western coast of North America causes some of the most torrential rains to occur in the region. Pineapple Express systems typically generate heavy snowfall in the mountains and Interior Plateau, which often melts rapidly because of the warming effect of the system. After being drained of their moisture, the tropical air masses reach the inland prairies as a Chinook wind or simply "a Chinook", a term which is also synonymous in the Pacific Northwest with the Pineapple Express.

Extreme cases

Many Pineapple Express events follow or occur simultaneously with major arctic troughs in the northwestern United States, often leading to major snow-melt flooding with warm, tropical rains falling on frozen, snow laden ground. Examples of this are the Christmas flood of 1964, Willamette Valley flood of 1996, New Year's Day Flood of 1997, January 2006 Flood in Northern California and Nevada, Great Coastal Gale of 2007, January 2008 Flood in Nevada, January 2009 Flood in Washington, the January 2012 Flood in Oregon, the 2019 Valentine's Day Flood in Southern California, and the February 2020 floods in Oregon and Washington.

West coast, 1862

Early in 1862, extreme storms riding the Pineapple Express battered the west coast for 45 days. In addition to a sudden snow melt, some places received an estimated 8.5 feet (2,600 mm) of rain, leading to the worst flooding in recorded history of California, Oregon, and Nevada, known as the Great Flood of 1862. Both the Sacramento and San Joaquin valleys flooded, and there was extensive flooding and mudslides throughout the region.

Northern California, 1952

The San Francisco Bay Area is another locale along the Pacific Coast which is occasionally affected by a Pineapple Express. When it visits, the heavy, persistent rainfall typically causes flooding of local streams as well as urban flooding. In the decades before about 1980, the local term for a Pineapple Express was "Hawaiian Storm". During the second week of January 1952, a series of "Hawaiian" storms swept into Northern California, causing widespread flooding around the Bay Area.

The same storms brought a blizzard of heavy, wet snow to the Sierra Nevada Mountains, notoriously stranding the train City of San Francisco on 13 January.

Northern California, 1955

The greatest flooding in Northern California since the 1800s occurred in 1955 as a result of a series of Hawaiian storms, with the greatest damage in the Sacramento Valley around Yuba City.

Southern California, 2005

Unusually high precipitation caused an ephemeral lake to occur in the Badwater Basin of Death Valley National Park, 2005.

Main article: Los Angeles County flood of 2005

A Pineapple Express related storm battered Southern California from January 7–11, 2005. This storm was the largest to hit Southern California since the storms that hit during the 1997–98 El Niño event. The storm caused mud slides and flooding, with one desert location just north of Morongo Valley receiving about 9 inches (230 mm) of rain, and some locations on south and southwest-facing mountain slopes receiving spectacular totals: San Marcos Pass, in Santa Barbara County, received 24.57 inches (624 mm), and Opids Camp (AKA Camp Hi-Hill) in the San Gabriel Mountains of Los Angeles County was deluged with 31.61 inches (803 mm) of rain in the five-day period. In some areas the storm was followed by over a month of near-continuous rain.

Alaska, 2006

The unusually intense rainstorms that hit south-central Alaska in October 2006 were called "Pineapple Express" rains locally.

Pacific Northwest, 2006

November 2006 flood, Granite Falls on the Stillaguamish River, Washington

The Puget Sound region from Olympia, Washington to Vancouver, British Columbia received several inches of rain per day in November 2006 from a series of successive Pineapple Express related storms that caused massive flooding in all major regional rivers and mudslides which closed the mountain passes. These storms included heavy winds which are not usually associated with the phenomenon. Regional dams opened their spillways to 100% as they had reached capacity because of rain and snowmelt. Officials referred to the storm system as "the worst in a decade" on 8 November 2006. Portions of Oregon were also affected, including over 14 inches (360 mm) in one day at Lees Camp in the Coast Range, while the normally arid and sheltered Interior of British Columbia received heavy, coastal-magnitude rains.

Southern California, December 2010

In December 2010, a Pineapple Express system ravaged California from 15 to 22 December, bringing with it as much as 2 feet (610 mm) of rain to the San Gabriel Mountains, and over 13 feet (4.0 m) of snow in the Sierra Nevada. Although the entire state was affected, the Southern California counties of San Bernardino, Orange, Riverside, San Diego, and Los Angeles bore the brunt of the system of storms, as coastal and hillside areas were impacted by mudslides and major flooding.

California, December 2014

In December 2014, a powerful winter storm enhanced by a Pineapple Express feature struck California, resulting in snow, wind, and flood watches. A blizzard warning was issued by the National Weather Service for the Northern Sierra Nevada for the first time in California since October 2009 and January 2008. The storm caused power outages for more than 50,000 people. It was thought to be the most powerful storm to impact California since the January 2010 California winter storms. A rare tornado touched down in Los Angeles on 12 December.

West Coast, 2017

Main article: 2017 California floods

Historically strong storms associated with the Pineapple Express brought flooding and mudslides to California, particularly the San Francisco Bay Area, destroying homes and closing numerous roads, including State Route 17, State Route 35, State Route 37, Interstate 80, State Route 12, State Route 1, State Route 84, State Route 9 and State Route 152.

The storm brought major snow to the Sierra Nevada and San Gabriel Mountains. A state record was recorded with places on the Sierra reaching up to 800 inches (20 m) of snow. The storm also brought not only significant flooding to the Los Angeles area and most of southern California (killing about 3 people), but also significant severe weather in that area.

California, January 2021

Main article: January 31 – February 3, 2021 nor'easter

A powerful winter storm channeled a Pineapple Express into California from 26 to 29 January. One person was injured in one of the mudslides in Northern California, and many structures suffered damage. The storm killed at least two people in California. A significant length of California State Route 1 along the Big Sur collapsed into the ocean after massive amounts of rain were dumped, causing a debris flow onto the highway, which in turn triggered the collapse. In Southern California, the storm triggered widespread flooding and debris flows, forcing the evacuations of thousands of people and also causing widespread property damage. Salinas received 4 in (100 mm) of rainfall for the entire event causing mudflows that forced 7,000 people to evacuate. Across the State of California, the storm knocked out power to an estimated 575,000 people at one point, according to power outage tracking maps and PG&E. In the mountainous parts of the state, the winter storm dropped tremendous amounts of heavy snow, with Mammoth Mountain Ski Area receiving 94 in (240 cm) within 72 hours, and a total of 107 in (270 cm) of snowfall for the entire event. Blizzard conditions were also recorded on parts of the Sierra Nevada. Very high wind gusts were also observed, with gusts over 100 mph (160 km/h) observed at Alpine Meadows, peaking at 126 mph (203 km/h).

Pacific Northwest, 2021

Main article: November 2021 Pacific Northwest floods

Heavy rains attributed to a Pineapple Express event heavily impacted the Puget Sound region from Bellingham, Washington into the British Columbia Interior and the Lower Mainland from 14 to 15 November. At the peak of the rainstorm on 15 November, Bellingham received 2.78 inches (71 mm) of rain while Hope, B.C. measured rainfall of 277.5 millimetres (10.93 in) from 14 to 15 November. The resulting floods and ensuing mass wasting events forced the closure of all major Canadian road connections to Vancouver, British Columbia including Highway 1, the Coquihalla, and the Sea to Sky Highway.

California, 2022–2023

Main article: 2022–2023 California floods

Heavy rains attributed to a Pineapple Express caused widespread flooding in the Bay Area.

California, February 2024

Main article: February 2024 California atmospheric river

 

A Pineapple Express storm hit the state from 1 to 2 February 2024, before moving over the United States and settling over the I-25 corridor in Colorado, where heavy snow fell. Another one hit 3 February and last until 5 February, with the National Weather Service calling it "potentially life-threatening." Other news sources estimated that Los Angeles received six-months' worth of rain in the 48-hour period, while the Sierra Nevada mountains got 1 to 3 ft (30 to 91 cm) of snow, with over 4 feet (120 cm) of snow expected in higher elevations, such as Mammoth Lakes, CA. Parts of the San Bernardino Mountains' foothills received 10 to 12 in (250 to 300 mm) of rain.