Several GPCRs contain polyproline motifs within their intracellular domains that mediate protein interactions with SH3 domains. For example, the third intracellular loop of pi-adrenergic receptors (pi-ARs) and p2-ARs are highly conserved except that pi-ARs contain a 24 amino acid polyproline motif in the middle of the loop. Thus this motif may in part be responsible for the differences in signalling exhibited by P-ARs. Protein interaction studies revealed that SH3p4/p8/p13, also known as endophilin 1/2/3, binds to the third intracellular loop of the pi-AR, but not the P2-AR (Tang et al. 1999). This interaction is mediated by binding of the C-terminal SH3 domain of SH3p4 to the pi-AR, and overexpression of SH3p4 promotes agonist-induced internalization and decreases the Gs coupling efficacy of pi-ARs in HEK293 cells, while having no effect on p2-ARs. Polyproline motifs are found in several other GPCRs including the p3-AR, the p2A-AR, and dopamine D4 receptors suggesting a previously unrecognized role for SH3-containing proteins in the regulation of GPCR signalling.
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