Pharmacology of GABA C receptors: responses to agonists and antagonists distinguish A- and B-subtypes of homomeric ρ receptors expressed in Xenopus oocytes

Abstract

GABA C receptors, expressed predominantly in vertebrate retina, are thought to be formed mainly by GABA ρ subunits. Five GABA ρ subunits have been cloned from white perch retina, four of which form functional homooligomeric receptors when expressed in Xenopus oocytes. These ρ subtypes, classified as ρ1A, ρ1B, ρ2A and ρ2B receptors based on amino acid sequence alignment, exhibit distinct temporal and pharmacological properties. To examine further the pharmacological properties associated with the various ρ receptor subtypes, we investigated the effects of a selective GABA C receptor antagonist, TPMPA, on the GABA-mediated activity of receptors formed in Xenopus oocytes by the four GABA ρ subunits. In addition, we recorded the activation profiles of β-alanine, taurine, and glycine, three amino acids that modulate neuronal activity in various parts of the CNS and are purported to be ρ receptor agonists. TPMPA effectively inhibited GABA-elicited responses on A-type receptors, whereas B-type receptors exhibited a relatively low sensitivity to the drug. A-type and B-type receptors also displayed distinctly different reactions to agonists. Both taurine and glycine-activated the B-type receptors, whereas these agents had no detectable effect on A-type receptors. Similarly, β-alanine evoked large responses from B-type receptors, but was far less effective on A-type receptors. These results indicate that, in addition to the characteristic response properties identified previously, there is a pattern of pharmacological reactions that further distinguishes the A- and B-subtypes of GABA ρ receptor.