1. Early and late D2 dopamine receptor signaling during slow synaptic transmission.
Early and late D2 dopamine receptor signaling during slow synaptic transmission. In the early phase of signaling, G protein-mediated signaling induces a rapid and transient change in the phosphorylation of direct or indirect PKA targets such as DARPP-32 and CREB. This early phase of D2 dopamine receptor signaling is rapidly antagonized after the inactivation of G proteins by RGSs. In addition, receptor phosphorylation by GRKs results in G protein uncoupling, recruitment of β-arrestins, and clathrin-dependent receptor internalization, effectively shutting down G protein-mediated signaling. In the late phase of signaling, the D2 dopamine receptors stimulate the formation of a protein complex composed of β-arrestin 2, PP2A, and Akt. Formation of this complex results in the deactivation of Akt by PP2A and the subsequent stimulation of GSK-3-mediated signaling. This second wave of signaling mediated by the Akt/β-arrestin 2PP2A complex results in a more progressive and longer lasting response (see inset graph). AP2, adaptor protein complex; DA, dopamine; D2R, D2 dopamine receptor. For a detailed description, see sections III.A, III.B, III.C, IV.E, and IV.F.
Jean-Martin Beaulieu, and Raul R. Gainetdinov Pharmacol Rev 2011;63:
© 2011 by The American Society for Pharmacology and Experimental Therapeutics