Functional modulation of GABAB receptors by protein kinases and receptor trafficking.

GABA(B) receptors (GABA(B)R) are heterodimeric G protein-coupled receptors (GPCRs) that mediate slow and prolonged inhibitory signals in the central nervous system. The signaling of GPCRs is under stringent control and is subject to regulation by multiple posttranslational mechanisms. The beta-adrenergic receptor is a prototypic GPCR. Like most GPCRs, prolonged exposure of this receptor to agonist induces phosphorylation of multiple intracellular residues that is largely dependent upon the activity of G protein-coupled receptor kinases (GRKs). Phosphorylation terminates receptor-effector coupling and promotes both interaction with beta-arrestins and removal from the plasma membrane via clathrin-dependent endocytosis. Emerging evidence for GABA(B)Rs suggests that these GPCRs do not conform to this mode of regulation. Studies using both native and recombinant receptor preparations have demonstrated that GABA(B)Rs do not undergo agonist-induced internalization and are not GRK substrates. Moreover, whilst GABA(B)Rs undergo clathrin-dependent constitutive endocytosis, it is generally accepted that their rates of internalization are not modified by prolonged agonist exposure. Biochemical studies have revealed that GABA(B)Rs are phosphorylated on multiple residues within the cytoplasmic domains of both the R1 and R2 subunits by cAMP-dependent protein kinase and 5'AMP-dependent protein kinase (AMPK). Here we discuss the role that this phosphorylation plays in determining GABA(B)R effector coupling and their trafficking within the endocytic pathway and go on to evaluate the significance of GABA(B)R phosphorylation in controlling neuronal excitability under normal and pathological conditions.
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