Dopamine responsiveness is regulated by targeted sorting of D2 receptors.
Aberrant dopaminergic signaling is a critical determinant in multiple psychiatric disorders, and in many disease states, dopamine receptor number is altered. Here we identify a molecular mechanism that selectively targets D2 receptors for degradation after their activation by dopamine. The degradative fate of D2 receptors is determined by an interaction with G protein coupled receptor-associated sorting protein (GASP). As a consequence of this GASP interaction, D2 responses in rat brain fail to resensitize after agonist treatment. Disruption of the D2-GASP interaction facilitates recovery of D2 responses, suggesting that modulation of the D2-GASP interaction is important for the functional down-regulation of D2 receptors.
Bartlett
Selena E
SE
Ernest Gallo Clinic and Research Center, University of California, San Francisco, CA 94608, USA.
Enquist
Johan
J
Hopf
Frederic W
FW
Lee
Josephine H
JH
Gladher
Fredrik
F
Kharazia
Viktor
V
Waldhoer
Maria
M
Mailliard
William S
WS
Armstrong
Randall
R
Bonci
Antonello
A
Whistler
Jennifer L
JL
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation; D004594:Electrophysiology; D005982:Glutathione Transferase; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
C463459:GPRASP1 protein, human; D017448:Receptors, Dopamine D2; D033921:Vesicular Transport Proteins; D049452:Green Fluorescent Proteins; D005982:Glutathione Transferase; D004298:Dopamine