Inhibitory neurotransmission in the mammalian central nervous system (CNS) is mediated by the amino acids γ-aminobutyric acid (GABA) and glycine. Glycine is mainly restrictively distributed in spinal cord and brain stem, whereas GABA is the major inhibitory neurotransmitter in the CNS. There are two main types of GABA receptors: fast-acting ionotropic GABAA and GABAC receptors, and slower-acting metabotropic GABAB receptors. So ionotropic GABA receptors can be classified into two subtypes: GABAA and GABAC receptors, based on the pharmacological characteristics. The third type of GABA receptor, GABAB receptor is a G protein-coupled receptor which modulates theconductance of Ca2+ and K+ channels via G-protein.
It has a very different molecular structure compared to GABAA and GABAC receptors. GABA is the common agonist of all three types of GABA receptors. GABAA receptors are competitively inhibited by bicuculline, whereas GABAC receptors are specificially blocked by (1,2,5,6-tetrahydropyridin-4-yl)methyl phosphonic acid (TPMPA). Both types of ionotropic GABA receptors can be non-competitively blocked by picrotoxin, a drug originally found in snake. Upon binding with a specific agonist, GABAA and GABAC receptors open the channels and increase the conductance to Cl-, which results in a hyperpolarity of the plasma membranes in most of the circumstances; however, in some stages of development or in some organs, the activation of ionotropic GABA receptors generates excitatory effects. GABAB receptors, on the contrary, normally produce hyperpolarity by increasing the conductance of K+ and inhibiting the elevation of cellular Ca2+, which results in a decrease of the membrane excitability and inhibits the releasing of neurotransmitters.
GABAA receptor is an oligomeric glycoprotein, which together with ligandgated receptors for the neurotransmitters glycine, acetylcholine (Ach) and 5-hydroxytryptamine, form an evolutionary superfamily of ligand-gated ion channels (LGICS) mediating fast synaptic transmission in the mammalian CNS. Excitatory signals are mediated by nicotinic acetylcholine receptor (nAChR) and type3 5-hydroxytryptamine (5-HT3) receptors. Inhibitory signals are mediated by GAB AA and glycine receptors. Briefly, GABAB receptors are metabotropic G-protein-linked receptors, coupled by intracellular signal transduction cascades to calcium and potassium channels. GABAB receptors are the site of action of the muscle relaxant, baclofen, and are insensitive to drugs that modulate GABAA receptors. When GABA binds to the GABAB receptor, there is an increase in potassium conductanceand a decrease in voltage-dependent calcium currents, resulting in hyperpolarization of the neuron and inhibition of neurotrans-mission. GABACreceptors are the newly identified member of the GABA receptor family. They are also linked to chloride channels, with distinct physiological and pharmacological properties. In contrast to the fast and transient responses elicited from GABAA receptors, GABACreceptors mediate slow and sustained responses. Pharmacologically, GABACreceptors are bicuculline- and baclofen-insensitive, and are not modulated by many GABAA receptor modulators (such as benzodiazepines and barbiturates).
That the GABAA receptors are of importance is due to the pivotal role that they play in the regulation of brain excitability and the fact that their function isallosterically regulated by several distinct classes of therapeutic compounds. These include anxiolytic benzodiazepines, barbiturates, neurosteroids and some volatile anesthetics. The first benzodiazepine drug, chlordiazepoxide, came to market for thetreatment of anxiety in 1960, only 30 months after the first observations of the verypotent anticonvulsant and taming effects in experimental animals. By the end of 1983, there were as many as 35 benzodiazepines or related drugs widely prescribed as anxiolytics. The great breakthrough in understanding of the mechanism of action of benzodiazepines came in the mid-1970s with two landmark discoveries. The first of these was the discovery that benzodiazepines influenced the GABA receptor functions, and that the action of benzodiazepines was to facilitate GABA ergic transmission. The second came with the identification of specific binding sites in rat brain membranes for [3H]-diazepam.
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Jin, Nili.Characterization and Functional Study of Ionotropic Gaba Receptors in Alveolar Epithelial Cells. Diss. Oklahoma State University, 2005.
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