Modulation of cell surface GABAB receptors by desensitization, trafficking and regulated degradation

Figure 3 Regulation of cell surface GABA_B receptors by trafficking. A: Under normal conditions GABA_B receptors are constitutively internalized and recycled back to the plasma membrane. Only a small fraction of receptors are sorted to lysosomes for degradation; B: Sustained activation of glutamate receptors [primarily 2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptors] and L-type voltage-gated Ca²⁺ channels raises intracellular Ca²⁺ levels. This induces phosphorylation of GABA_B1 at serine 867 by calmodulin-dependent protein kinaseII (CaMKII) and of GABA_B2 at serine 783 by adenosine monophosphate (AMP) kinase, followed by slow dephosphorylation, by protein phosphatase 2 (PPA2). These events shift the recycling/degradation equilibrium towards degradation so that the majority of GABA_B receptors are no longer recycled, but instead degraded in lysosomes. Since constitutive endocytosis of the receptors remains unaffected, this mechanism results in a rapid down-regulation of GABA_B receptors. AMPK: 5’AMP-dependent protein kinase; GABA: γ-Aminobutyric acid; VSCCs: Voltage-sensitive calcium channels.