Two sites in the third inner loop of the dopamine D₂ receptor are involved in functional G protein-mediated coupling to adenylate cyclase

Synthetic peptides, corresponding to the amino acid sequences of the N- and C-terminal parts of the 3rd intracellular loop of the dopamine D₂ receptor, attenuate dopaminergic adenylate cyclase inhibition in membranes. Both peptides also activate directly GTPase activity in membranes. We suggest a functional model for G_i-coupled receptors where two sites in the 3rd inner loop compose the links for the receptor-G protein interaction thus providing the tools for a selective and adjustable response. Functional coupling was not affected by a peptide representing the insert in the long form of the dopamine D; receptor (D_2(long)). The selectivity pattern of conventional G protein-linked receptors also sheds some light on the recently observed interaction of β-amyloid protein precursor (APP) complexes with G proteins.