Role of intracellular loops of cannabinoid CB(1) receptor in functional interaction with G(alpha16)

The cannabinoid CB(1) but not the CB(2) receptor was demonstrated to couple via G(alpha16) to activate phospholipase C after co-expression in COS7 cells. Chimeric CB(1)/CB(2) receptors were used as a model to study receptor-G(alpha16) interaction. Sequences of the second and third intracellular loops and the carboxy-terminus were substituted from the CB(1) into the CB(2) receptor. Only the triple mutant with all three regions replaced activated phospholipase C to a similar extent as the CB(1) receptor, suggesting that all three intracellular regions are required for interacting with G(alpha16). Several sub-domains within the third intracellular loop were identified for receptor-G(alpha16) interaction.