Stephen J. Moss Laboratory

GABA_Β

In contrast to the majority of other G-protein coupled receptors (GPCRs), the formation of functional GABA_Β receptors is dependent upon the assembly of functional heterodimers composed of GABA_ΒR1 and R2 subunits (Couve et al., 2004). Given the unique structure of GABA_Β receptors we are currently examining the cellular mechanisms neurons use to control the function of these atypical GPCRs.

Our results have revealed that GABA_Β receptors, in contrast to the monomeric GPCRs as typified by studies on the β-adrenergic receptor, undergo agonist-induced phosphorylation and desensitization and consequently exhibit half-lives of approximately 30h on the surface of neurons (Fairfax et al., 2004; Couve et al., 2004). It is also evident that direct phosphorylation of GABA_Β receptors within the cytoplasmic tail of the GABA_Β R2 subunit by cAMP-dependent, or AMP-dependent protein kinases is a powerful modulator of their functional coupling to effectors such as K+ channels. However, in contrast to monomeric GPCRs direct phosphorylation by these kinases reduces GABA_Β receptor desensitization promoting their functional coupling (Couve et al., 2002; 2004).

To address the significance of this novel mode of GPCR regulation we are studying GABA_Β receptor function in mice in which specific sites of phosphorylation with either the receptor R1 and R2 subunits have been mutated.

Last Updated: 7-apr-06