From ion currents to genomic analysis: Recent advances in GABAA receptor research
Article first published online: 12 OCT 2004
Copyright © 1995 Wiley-Liss, Inc.
Volume 21, Issue 3, pages 189–274, November 1995
How to Cite
Rabow, L. E., Russek, S. J. and Farb, D. H. (1995), From ion currents to genomic analysis: Recent advances in GABAA receptor research. Synapse, 21: 189–274. doi: 10.1002/syn.890210302
- Issue published online: 12 OCT 2004
- Article first published online: 12 OCT 2004
- Manuscript Revised: 20 JAN 1995
- Manuscript Accepted: 20 JAN 1995
- Manuscript Received: 15 NOV 1994
- Ion channel;
- GABAA receptor;
- Gene expression
The γ-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 (αl-α6, βl-β4, γl-γ4,δ, pl-p2) and alternatively spliced variants contribute to the molecular architecture of the GABAA receptor. Mysteriously, certain preferred combinations of subunits, most notably the αlβ2γ2 arrangement, are widely codistributed, while the expression of other subunits, such as βl or α6, 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.