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

gamma-Aminobutyric acid type B receptors (GABA(B)Rs) are involved in the fi ne tuning of inhibitory synaptic transmission. Presynaptic GABA(B)Rs inhibi t neurotransmitter release by down-regulating high-voltage activated Ca2+ c hannels, whereas postsynaptic GABA(B)Rs decrease neuronal excitability by a ctivating a prominent inwardly rectifying K+ (Kir) conductance that underli es the late inhibitory postsynaptic potentials. Here we report the cloning and functional characterization of two human GABA(B)Rs, hGABA(B)R1a (hR1a) and hGABA(B)R1b (hR1b). These receptors closely match the pharmacological p roperties and molecular weights of the most abundant native GABA(B)Rs, We s how that in transfected mammalian cells hR1a and hR1b can modulate heterome ric Kir3.1/3.2 and Kir3.1/3.4 channels. Heterologous expression therefore s upports the notion that Kir3 channels are the postsynaptic effecters of GAB A(B)Rs;. Our data further demonstrate that in principle either of the clone d 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 associ ation of hR1b, and not hR1a, with postsynaptic Kir3 channels. The mapping o f the GABA(B)R1 gene to human chromosome 6p213, in the vicinity of a suscep tibility locus (EJM1) for idiopathic generalized epilepsies, identifies a c andidate gene for inherited forms of epilepsy.