Review
Structure and function of GABAC receptors: a comparison of native versus recombinant receptors

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Abstract

In less than a decade our knowledge of the GABAC receptor, a new type of Cl–-permeable ionotropic GABA receptor, has greatly increased based on studies of both native and recombinant receptors. Careful comparison of properties of native and recombinant receptors has provided compelling evidence that GABA receptor ρ-subunits are the major molecular components of GABAC receptors. Three distinct ρ-subunits from various species have been cloned and the pattern of their expression in the retina, as well as in various brain regions, has been established. The pharmacological profile of GABAC receptors has been refined and more specific drugs have been developed. Molecular determinants that underlie functional properties of the receptors have been assigned to specific amino acid residues in ρ-subunits. This information has helped determine the subunit composition of native receptors, as well as the molecular basis underlying subtle variations among GABAC receptors in different species. Finally, GABAC receptors play a unique functional role in retinal signal processing via three mechanisms: (1) slow activation; (2) segregation from other inhibitory receptors; and (3) contribution to multi-neuronal pathways.

Section snippets

Genes, phylogeny and primary structure of ρ-subunits

To date, full-length cDNAs for GABA receptor ρ-subunits have been cloned from human, rat, mouse and fish by several laboratories 21, 36, 42, 43, 44, 45, 46, whereas partial sequences have been obtained from chicken 47. Three specific types of ρ-subunits, ρ1–ρ3, have been identified by multiple sequence alignment, phylogenetic analysis and physiological studies. The sequence identity across species is highest among ρ1-subunits and lowest among ρ3-subunits, which suggests a phylogenetic

Agonists

GABAC receptors share several agonists with GABAA receptors (Fig. 3). However, the sensitivity of GABAC receptors to GABA is much higher than that of GABAA receptors, with EC50 values in the range 0.8–2.2 μm for recombinant ρ1 or ρ2 homomeric receptors 36, 37, 46, 61, 63, 64, and 7.5 μm for ρ3 homomeric receptors 65. The EC50 of GABAC receptor responses of retinal neurons is similar to or slightly higher than that of recombinant ρ1 or ρ2 receptors 23, 66. The conformationally restricted GABA

Molecular determinants of GABAC receptor pharmacology and physiology

The specific amino acid residues that underlie a variety of pharmacological and physiological properties of GABAC receptors have been determined by combining electrophysiological and molecular biological techniques. These amino acid residues are highly conserved among various species (Fig. 2). Different laboratories have used disparate numbering systems for the amino acid sequences of the various ρ-subunits. To compare these sequences, here we refer to residue positions on the basis of amino

Physiological functions of GABAC receptors

What is the physiological function of GABAC receptors in the CNS? Knowledge about the function of GABAC receptors has been derived mainly from studies in the retina, where GABAC receptors are predominantly expressed. Nonetheless, understanding the function of GABAC receptors in the retina might provide insight into their role in the CNS in general. Similar to other areas of the CNS, GABA is a major inhibitory neurotransmitter in the retina 109, 110. GABAA receptors were extensively studied in

Definition of the ‘GABAC’ receptor

Functionally, it might be reasonable to label bicuculline-insensitive or benzodiazepine-insensitive GABA receptors as GABAC receptors, at least in the retina. However, the use of these pharmacological criteria alone might not be sufficient because altered sensitivity to bicuculline and barbiturate has been observed in recombinant GABAA and GABAC mutant receptors with single amino acid mutations 105, 121. There is abundant evidence to suggest that ρ-subunits are probably the major, if not the

Concluding remarks

In less than a decade, the cloning and characterization of ρ-subunits have contributed remarkably to our current understanding of the molecular basis for GABAC receptors. Comparing functional properties of recombinantly expressed ρ-subunits with GABAC receptor responses of native neurons has provided compelling evidence that this novel subtype of GABA receptor exists in several regions of the CNS and is of functional importance, at least in the retina. It is impressive that the diversity of

Chemical name

SR95531: 2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium

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