Selectivity and functional consequences of interactions of family A G protein-coupled receptors with neurochondrin and periplakin

A wide range of intracellular proteins have been demonstrated to interact with individual G protein-coupled receptors (GPCRs) and, in certain cases, to modulate their function or trafficking. However, in only a few cases have the GPCR selectivity of such interactions been investigated. Interactions between the intracellular C-terminal tails of 44 GPCRs and both neurochondrin and periplakin were assessed in pull-down studies. 23 of these interacted with neurochondrin and periplakin, 10 interacted with neither whilst nine interacted with only neurochondrin and two with only periplakin. When appropriate GIP-interacting G_q/G₁₁-coupled GPCRs were expressed in cells inducibly expressing neurochondrin or periplakin this resulted in a reduction in the increase in intracellular [Ca²⁺] in response to agonist. However, induction of neurochondrin or periplakin was without functional consequences for GPCRs with which they did not interact. Unlike intracellular [Ca²⁺] signals, induction of expression of either interacting protein did not inhibit agonist-mediated ERK1/2 MAPK phosphorylation. These data indicate that both periplakin and neurochondrin can interact with a wide range of GPCRs and modulate function selectively. Details of the structure of the intracellular C-terminal tail of individual receptors will be required to fully understand the basis of such selectivity.