Human γ-aminobutyric acid type B receptors are differentially expressed and regulate inwardly rectifying K⁺ channels

Abstract

γ-Aminobutyric acid type B receptors (GABA_BRs) are involved in the fine tuning of inhibitory synaptic transmission. Presynaptic GABA_BRs inhibit neurotransmitter release by down-regulating high-voltage activated Ca²⁺ channels, whereas postsynaptic GABA_BRs decrease neuronal excitability by activating a prominent inwardly rectifying K⁺ (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Here we report the cloning and functional characterization of two human GABA_BRs, hGABA_BR1a (hR1a) and hGABA_BR1b (hR1b). These receptors closely match the pharmacological properties and molecular weights of the most abundant native GABA_BRs. We show that in transfected mammalian cells hR1a and hR1b can modulate heteromeric Kir3.1/3.2 and Kir3.1/3.4 channels. Heterologous expression therefore supports the notion that Kir3 channels are the postsynaptic effectors of GABA_BRs. Our data further demonstrate that in principle either of the cloned receptors could mediate inhibitory postsynaptic potentials. We find that in the cerebellum hR1a and hR1b transcripts are largely confined to granule and Purkinje cells, respectively. This finding supports a selective association of hR1b, and not hR1a, with postsynaptic Kir3 channels. The mapping of the GABA_BR1 gene to human chromosome 6p21.3, in the vicinity of a susceptibility locus (EJM1) for idiopathic generalized epilepsies, identifies a candidate gene for inherited forms of epilepsy.