The GABA_A receptor is one of two ligand-gated ion channels responsible for mediating the effects of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. The Ligand-gated ion channels, also referred to as LGICs, or ionotropic receptors, are a group of intrinsic transmembrane ion channels that are Ion channels are pore-forming Proteins that help establish and control the small Voltage Gradient across the Plasma membrane of all living Gamma-aminobutyric acid (GABA is the chief inhibitory Neurotransmitter in the Mammalian Central nervous system. See Chemical synapse for an introduction to concepts and terminology used in this article The GABA_A receptor complex is also the molecular target of the benzodiazepine class of tranquilizer drugs, and hence it is also often referred to as the benzodiazepine receptor (although the benzodiazepines do not bind to the same receptor site as the endogenous ligand, GABA). The benzodiazepines (pronounced, often abbreviated to "benzos") are a class of Psychoactive drugs with varying Hypnotic

In addition to the GABA and benzodiazepine binding sites, the GABA_A receptor complex appears to have distinct binding sites for furosemide, neuroactive steroids, picrotoxin, barbiturates, ethanol, kavalactones, GHB, and inhalational anaesthetics. Furosemide ( INN) or frusemide (former BAN) is a Loop diuretic used in the treatment of congestive Heart failure and Edema Neuroactive Steroids (or neurosteroids') rapidly alter Neuronal excitability through interaction with Neurotransmitter[[ligand gated ion channel|-gated Picrotoxin, also known as cocculin, is a poisonous crystalline plant alkaloid first isolated by Boullay in 1812 Barbiturates are drugs that act as central nervous system Depressants and by virtue of this they produce a wide spectrum of effects from mild Sedation Kavalactones are the main psychoactive components of the roots of Piper methysticum (kava a shrub common on some Pacific Ocean islands gamma -Hydroxybutyric acid, 4-hydroxybutanoic acid, GHB, or fantasy is a naturally-occurring substance found in the Central nervous Inhalational anaesthetics are gases or Vapours possessing Anaesthetic qualities ^[1]

Contents 1 Structure and function 1.1 Subunits 2 Agonists, antagonists, and inverse agonists 2.1 Agonists 2.2 Antagonists 2.3 Inverse agonists 2.4 Subtype selective ligands 3 See also 4 References 5 External links

Structure and function

The receptor is a multimeric transmembrane receptor that consists of five subunits arranged around a central pore. In Chemistry, an oligomer consists of a limited number of Monomer units (ολιγος or oligos is Greek for "a few" in contrast to a Transmembrane receptors are Integral membrane proteins which reside and operate typically within a cell's Plasma membrane, but also in the membranes of The receptor sits in the membrane of its neuron at a synapse. The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information Chemical synapses are specialized junctions through which Neurons signal to each other and to non-neuronal cells such as those in Muscles or Glands 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 ions (Cl⁻) to pass down an electrochemical gradient. In Chemistry, a ligand is either an Atom, Ion, or Molecule (see also Functional group) that bonds to a central metal generally The word endogenous means "arising from within" the opposite of Exogenous. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl The chloride Ion is formed when the element Chlorine picks up one Electron to form an Anion (negatively-charged ion Cl&minus An ion is an Atom or Molecule which has lost or gained one or more Valence electrons giving it a positive or negative electrical charge Membrane potential (or transmembrane potential) is the Voltage difference (or Electrical potential difference between the interior and exterior of a Because the reversal potential for chloride in most neurons is close to or more negative than the resting membrane potential, activation of GABA_A receptors tends to stabilize the resting potential, and can make it more difficult for excitatory neurotransmitters to depolarize the neuron and generate an action potential. In a Biological membrane, the reversal potential (also known as the Nernst potential) of an Ion is the Membrane potential at which there Membrane potential (or transmembrane potential) is the Voltage difference (or Electrical potential difference between the interior and exterior of a See Chemical synapse for an introduction to concepts and terminology used in this article In biology depolarization is a decrease in the Absolute value of a cell's Membrane potential. In Neurophysiology, the action potential is a self-regenerating Wave of Electrochemical activity that allows Nerve cells to carry a signal The net effect is typically inhibitory, reducing the activity of the neuron. The GABA_A channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP). An Inhibitory Postsynaptic Potential (commonly abbreviated as IPSP) is the change in membrane voltage of a postsynaptic Neuron which results from synaptic ^[2][3] The endogenous ligand that binds to the benzodiazepine receptor is inosine. Inosine is a Nucleoside that is formed when Hypoxanthine is attached to a Ribose ring (also known as a Ribofuranose) via a β-N9-

Subunits

GABA_A receptors are members of the large "Cys-loop" super-family of evolutionarily related and structurally similar ligand-gated ion channels that also includes nicotinic acetylcholine receptors, glycine receptors, and the 5HT₃ receptor. The Ligand-gated ion channels, also referred to as LGICs, or ionotropic receptors, are a group of intrinsic transmembrane ion channels that are Structure Nicotinic receptors with a molecular mass of 290 kDa, are made up of five subunits arranged symmetrically around the central pore. The glycine receptor, or GlyR, is the receptor for the Amino acid Neurotransmitter Glycine. The 5-HT3 receptor is a member of the superfamily of Ligand-gated ion channels a superfamily that also includes the neuronal Nicotinic acetylcholine receptors There are numerous subunit isoforms for the GABA_A receptor, which determine the receptor’s agonist affinity, chance of opening, conductance, and other properties. A protein isoform is a version of a Protein with only small differences to another isoform of the same protein ^[4]

In humans, the units are as follows:^[5]

• six types of α subunits (GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6)
• three β's (GABRB1, GABRB2, GABRB3)
• three γ's (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,^[6] but rather homooligomerize to form GABA_C receptors. Gamma-aminobutyric acid (GABA A receptor alpha 1, also known as GABRA1, is a human Gene. Gamma-aminobutyric acid (GABA A receptor alpha 2, also known as GABRA2, is a human Gene. Gamma-aminobutyric acid (GABA A receptor alpha 3, also known as GABRA3, is a human Gene. Gamma-aminobutyric acid (GABA A receptor alpha 4, also known as GABRA4, is a human Gene. Gamma-aminobutyric acid (GABA A receptor alpha 5, also known as GABRA5, is a human Gene. Gamma-aminobutyric acid (GABA A receptor alpha 6, also known as GABRA6, is a human Gene. Gamma-aminobutyric acid (GABA A receptor beta 1, also known as GABRB1, is a human Gene. Gamma-aminobutyric acid (GABA A receptor beta 2, also known as GABRB2, is a human Gene. Gamma-aminobutyric acid (GABA A receptor beta 3, also known as GABRB3, is a human Gene. Gamma-aminobutyric acid (GABA A receptor gamma 2, also known as GABRG2, is a human Gene. Gamma-aminobutyric acid (GABA A receptor gamma 3, also known as GABRG3, is a human Gene. Gamma-aminobutyric acid (GABA A receptor delta, also known as GABRD, is a human Gene. Gamma-aminobutyric acid (GABA A receptor epsilon, also known as GABRE, is a human Gene. Gamma-aminobutyric acid (GABA A receptor pi, also known as GABRP, is a human Gene. Gamma-aminobutyric acid (GABA receptor rho 1, also known as GABRR1, is a human Gene. Gamma-aminobutyric acid (GABA receptor rho 2, also known as GABRR2, is a human Gene. The GABAC receptor is one of two Ligand-gated ion channels responsible for mediating the effects of Gamma-Amino Butyric Acid ( GABA) the major inhibitory

Five subunits can combine in different ways to form GABA_A channels, but the most common type in the brain is a pentamer comprising two α's, two β's, and a γ (α₂β₂γ). ^[5]

The receptor binds two GABA molecules,^[7] at the interface between an α and a β subunit. ^[5]

Agonists, antagonists, and inverse agonists

Other ligands (besides GABA) interact with the GABA_A receptor to increase chloride conductance (agonists), decrease conductance (inverse agonists) or to bind to the receptor and have no effect other than to prevent the binding of agonists or inverse agonists (antagonists). An agonist is a term used to describe a type of ligand or drug that binds and alters the activity of a receptor. In Pharmacology, an inverse agonist is an agent which binds to the same receptor binding-site as an Agonist for that receptor and reverses constitutive A receptor antagonist is a type of receptor ligand or Drug that does not provoke a biological response itself upon binding to a receptor, but blocks Hence ligands for the GABA_A receptor span a range of effects from full agonism to antagonism to inverse agonism.

Agonists

Full agonists display a large number of effects including anti-anxiety (anxiolytic), muscle relaxant, sedation, anti-convulsion, and at high enough doses, anaesthesia. An anxiolytic is a drug prescribed for the treatment of Symptoms of Anxiety. Sedation is a Medical procedure involving the administration of Sedative drugs generally to facilitate a medical procedure with Local anaesthesia. The anticonvulsants, also called antiepileptic drugs (abbreviated "AEDs" are a diverse group of pharmaceuticals used in the treatment of epileptic Anesthesia, or anaesthesia (see spelling differences; from Greek grc αν- an-, "without" and grc αἲσθησις Partial agonists may display a subset of these properties (for example anxiolytic without sedation).

Such other agonist ligands include

• benzodiazepines (increase pore opening frequency; often the active ingredient of sleep pills and anxiety medications)
• nonbenzodiazepines (newer class of sleep / anti-anxiety medications)
• barbiturates (increase pore opening duration; used as sedatives)
• kavalactones (psychoactive compounds found in the roots of the kava plant)^[8]
• certain steroids, called neuroactive steroids^{[9][10][11][12][13][14][15][16][17][18]}

Muscimol is an agonist used to distinguish GABA_A from the GABA_B receptor. The benzodiazepines (pronounced, often abbreviated to "benzos") are a class of Psychoactive drugs with varying Hypnotic A sedative, or more specifically a sedative-hypnotic, is a substance that depresses the Central nervous system (CNS resulting in calmness relaxation sleepiness An anxiolytic is a drug prescribed for the treatment of Symptoms of Anxiety. The nonbenzodiazepines are comparatively new drugs whose actions are somewhat similar to those of the Benzodiazepines but are structurally unrelated to the Benzodiazepines Barbiturates are drugs that act as central nervous system Depressants and by virtue of this they produce a wide spectrum of effects from mild Sedation A sedative, or more specifically a sedative-hypnotic, is a substance that depresses the Central nervous system (CNS resulting in calmness relaxation sleepiness Kavalactones are the main psychoactive components of the roots of Piper methysticum (kava a shrub common on some Pacific Ocean islands KAVA (1480 AM) is a Radio station broadcasting a Regional Mexican format A steroid is a Terpenoid Lipid characterized by a Carbon skeleton with four fused rings generally arranged in a 6-6-6-5 fashion Neuroactive Steroids (or neurosteroids') rapidly alter Neuronal excitability through interaction with Neurotransmitter[[ligand gated ion channel|-gated Muscimol ( Agarin, Pantherine) is the major Psychoactive alkaloid present in many mushrooms of the Amanita genus GABAB receptors (GABABR are Metabotropic Transmembrane receptors for Gamma-aminobutyric acid (GABA that are linked via G-proteins

Antagonists

Among antagonists are

• picrotoxin (non-competitive; binds the channel pore, effectively blocking any ions from moving through it)
• bicuculline (competitive; transiently occupies the GABA binding site, thus preventing GABA from activating the receptor)
• cicutoxin and oenanthotoxin, poisons found in certain Northern Hemisphere plants that grow in boggy soils. Picrotoxin, also known as cocculin, is a poisonous crystalline plant alkaloid first isolated by Boullay in 1812 Bicuculline (BIC is a light-sensitive competitive antagonist of GABAA receptors Cicutoxin (chemical name (8E10E12E14R-heptadeca-81012-trien-46-diyne-114-diol formula C17H22O2 is a Poisonous Polyyne Oenanthotoxin is a Toxin extracted from Hemlock water dropwort ( Oenanthe crocata) and other plants of the genus Oenanthe.
• flumazenil which is used medically to reverse excessive effects of the benzodiazepines. Flumazenil (also known as flumazepil, code name Ro 15-1788, trade names Anexate, Lanexat, Mazicon, Romazicon

Inverse agonists

Full inverse agonists have convulsive properties while partial inverse agonists may be useful as aids in memory and learning. An example of a partial inverse agonist is Ro15-4513. Ro15-4513 is a weak partial Inverse agonist of the Benzodiazepine class of drugs developed by Hoffmann–La Roche in 1984 and is structurally related

Subtype selective ligands

A useful property of the many benzodiazepine receptor ligands 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 affects from undesirable side effects. Few subtype selective ligands have gone into clinical use as yet, but some examples of these compounds which are widely used in scientific research are Bretazenil (subtype-selective partial agonist), Imidazenil (partial agonist at some subtypes, weak antagonist at others) and QH-ii-066 (full agonist highly selective for α₅ subtype). Bretazenil is an Anxiolytic drug which is derived from the Benzodiazepine family and was invented in 1988 Imidazenil is an Anxiolytic drug which is derived from the Benzodiazepine family and is most closely related to other imidazobenzodiazepines such as Midazolam QH-II-66 (QH-ii-066 is a Sedative drug which is a Benzodiazepine derivative

See also

• GABA receptor
• GABA_B receptor
• GABA_C receptor
• Glycine receptor

References

External links

• Basic Neurochemistry: GABA Receptor Physiology and Pharmacology
• Dr. Dreyer's GABA-R webpage (University of Fribourg, Switzerland)

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