A novel γ-aminobutyric acid receptor subunit (ρ2) cloned from human retina forms bicuculline-insensitive homooligomeric receptors in Xenopus oocytes

Abstract

The ρ2 subunit, a novel GABA receptor subunit, has been cloned from a human retinal complementary DNA library. This subunit shares 74% amino acid sequence identity with the ρ1 subunit that forms homooligomeric bicuculline-, barbiturate-, and benzodiazepine-insensitive GABA receptors. The ρ2 subunit also forms homooligomeric GABA-activated chloride channels when expressed in Xenopus oocytes. The amplitudes of the whole-cell currents of ρ2 receptors are always smaller than those of ρ1 receptors, but the affinity and cooperativity of GABA are very similar. Like the ρ1 subunit, the currents generated by ρ2 are insensitive to GABA(A) receptor modulators including bicuculline, hexobarbital, and diazepam and can be reversibly inhibited by ZnCl2. Homooligomeric ρ2 and ρ1 receptors are less sensitive to muscimol and picrotoxin, and desensitize slower than GABA(A) receptors. These data demonstrate that homooligomeric receptors formed by ρ2 and ρ1 subunits have a number of electrophysiologic and pharmacologic characteristics that differ from receptors formed by GABA(A) receptor subunits. The distinctive properties of ρ receptors are very similar to those of bicuculline-insensitive GABA-gated chloride channels identified in retina, suggesting a molecular basis for this form of GABA receptor in visual pathways.