Response kinetics and pharmacological properties of heteromeric receptors formed by coassembly of GABA rho- and gamma2-subunits

Abstract

Two of the γ–aminobutyric acid (GABA) receptors, GABA_A and GABA_C, are ligand–gated chloride channels expressed by neurons in the retina and throughout the central nervous system. The different subunit composition of these two classes of GABA receptor result in very different physiological and pharmacological properties. Although little is known at the molecular level as to the subunit composition of any native GABA receptor, it is thought that GABA_C receptors are homomeric assemblies of ρ–subunits. However, we found that the kinetic and pharmacological properties of homomeric receptors formed by each of the ρ–subunits cloned from perch retina did not resemble those of the GABA_C receptors on perch bipolar cells. Because both GABA_A and GABA_C receptors are present on retinal bipolar cells, we attempted to determine whether subunits of these two receptor classes are capable of interacting with each other. We report here that, when coexpressed in Xenopus oocytes, heteromeric (ρ_1Bγ₂) receptors formed by coassembly of the ρ_1B–subunit with the γ₂–subunit of the GABA_A receptor displayed response properties very similar to those obtained with current recordings from bipolar cells. In addition to being unresponsive to bicuculline and diazepam, the time–constant of deactivation, and the sensitivities to GABA, picrotoxin and zinc closely approximated the values obtained from the native GABA_C receptors on bipolar cells. These results provide the first direct evidence of interaction between GABA ρ and GABA_A–receptor subunits. It seems highly likely that coassembly of GABA_A and ρ–subunits contributes to the molecular organization of GABA_C receptors in the retina and perhaps throughout the nervous system.