From ion currents to genomic analysis: Recent advances in GABA_A receptor research

Abstract

The gamma-aminobutyric acid type A (GABAA) receptor represents an elementary switching mechanism integral to the functioning of the central nervous system and a locus for the action of many mood- and emotion-altering agents such as benzodiazepines, barbiturates, steroids, and alcohol. Anxiety, sleep disorders, and convulsive disorders have been effectively treated with therapeutic agents that enhance the action of GABA at the GABAA receptor or increase the concentration of GABA in nervous tissue. The GABAA receptor is a multimeric membrane-spanning ligand-gated ion channel that admits chloride upon binding of the neurotransmitter GABA and is modulated by many endogenous and therapeutically important agents. Since GABA is the major inhibitory neurotransmitter in the CNS, modulation of its response has profound implications for brain functioning. The GABAA receptor is virtually the only site of action for the centrally acting benzodiazepines, the most widely prescribed of the anti-anxiety medications. Increasing evidence points to an important role for GABA in epilepsy and various neuropsychiatric disorders. Recent advances in molecular biology and complementary information derived from pharmacology, biochemistry, electrophysiology, anatomy and cell biology, and behavior have led to a phenomenal growth in our understanding of the structure, function, regulation, and evolution of the GABAA receptor. Benzodiazepines, barbiturates, steroids, polyvalent cations, and ethanol act as positive or negative modulators of receptor function. The description of a receptor gene superfamily comprising the subunits of the GABAA, nicotinic acetylcholine, and glycine receptors has led to a new way of thinking about gene expression and receptor assembly in the nervous system. Seventeen genetically distinct subunit subtypes (alpha 1-alpha 6, beta 1-beta 4, gamma 1-gamma 4, delta, p1-p2) and alternatively spliced variants contribute to the molecular architecture of the GABAA receptor. Mysteriously, certain preferred combinations of subunits, most notably the alpha 1 beta 2 gamma 2 arrangement, are widely codistributed, while the expression of other subunits, such as beta 1 or alpha 6, is severely restricted to specific neurons in the hippocampal formation or cerebellar cortex. Nervous tissue has the capacity to exert control over receptor number, allosteric uncoupling, subunit mRNA levels, and posttranslational modifications through cellular signal transduction mechanisms under active investigation. The genomic organization of the GABAA receptor genes suggests that the present abundance of subtypes arose during evolution through the duplication and translocations of a primordial alpha-beta-gamma gene cluster. This review describes these varied aspects of GABAA receptor research with special emphasis on contemporary cellular and molecular discoveries.

Responses to GABAA receptor activation are altered in NTS neurons isolated from chronic hypoxic rats

“…1 GABA A receptors are the ubiquitous ligand-gated chloride ionophores responsible for most rapid inhibition within the central nervous system. [2][3][4] Within the NTS, activation of GABA A receptors inhibits virtually all neurons tested and results in an increase in arterial pressure, heart rate, and sympathetic outflow, effects consistent with inhibitory modulation of arterial baroreceptor reflexes. 1 The function of GABA A receptors has been shown to be modulated by a variety of factors.…”

“…Receptor number, subunit composition, and phosphorylation state are but a few of the ways that GABA receptor function can be altered after chronic exposure to alcohol, barbiturates, benzodiazepines, and GABA itself. [2][3][4] Alterations in the responses of NTS neurons to GABA A receptor activation could result in alterations in the integration of afferent inputs, reflex function, and resting cardiovascular parameters. The goal of the current study was to determine if the responses of isolated NTS neurons to activation of GABA A receptors are altered in hypertension.…”

GABAergic Interneurons Implications for Understanding Schizophrenia and Bipolar Disorder

“…Addition of the benzodiazepine, diazepam, resulted in a greater increase in binding in the schizophrenics. One limitation of this study was the fact that GABA was used as a competitive inhibitor, rather than bicuculline, a specific antagonist of the GABA A receptor (Rabow and Farb 1995), making it unclear as to whether the results reflect changes in this latter receptor or possibly the GABA B receptor and, perhaps, even the GABA transporter.…”

“…The inhibitory interneurons thus activated inhibit principal neurons, including those that directly excited them. Intracellular recordings from cortical pyramidal cells typically show a depolarization of brief duration that is followed by a longer lasting hyperpolarization (Sillito 1975); it is the latter component of this complex that reflects the action of GABA on the GABA A -chloride ionophore complex expressed by most postsynaptic neurons (Rabow and Farb 1995). Such an arrangement provides a "fail safe" mechanism that ensures pyramidal neurons do not fire excessively.…”

Functional properties of the human ventral mesencephalic neural stem cell line hVM1

“…Normally, GABA hyperpolarizes neurons, driving the membrane potential away from what would activate voltage-dependent calcium channels (Rabow et al, 1995). However, in immature neurons, GABA acts as depolarizing transmitter due to higher chloride concentration inside the cells as compared to outside (Cherubini et al, 1991;Rivera et al, 1999).…”