Dopamine responsiveness is regulated by targeted sorting of D2 receptors

Abstract

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 receptorassociated 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 downregulation of D2 receptors.

Dopaminergic modulation of neurogenesis in the subventricular zone of the adult brain

“…28 In the SVZ, NPCs express both of these receptor subtypes and thus depending on the extent of specific dopamine receptor stimulation, an altered signalling profile results. 29 From a therapeutic perspective, knowledge of the dopaminergic agonist combination that maximally stimulates neuronal differentiation could potentially be of great benefit for future therapies that focus on upregulating or manipulating endogenous neurogenesis for diseases that affect the dopaminergic system, such as PD.…”

Increased desensitization of dopamine D2 receptor-mediated response in the ventral tegmental area in the absence of adenosine A2A receptors

“…Based on this model, it is therefore possible to speculate that A 2A receptors may interface between D 2 receptors and G-protein-coupled receptor-associated sorting proteins (Bartlett et al, 2005) to facilitate membrane insertion of D 2 receptors. Indeed in the A 2A receptor knockout mice, D 2 receptor expression at the mRNA level were found increased, but not the number of functional receptors (Chen et al, 2001;Dassesse et al, 2001;Bailey et al, 2004a;Short et al, 2006).…”

Autophagy activation by novel inducers prevents BECN2-mediated drug tolerance to cannabinoids

“…33,34 Briefly, HEK293 cells stably expressing FLAG-CNR1 were grown on chamber slides, and incubated with 3.5 mg/ml M1 anti-FLAG antibody (Sigma-Aldrich, F3040) for 30 min. The cells were either directly fixed and immunostained as below as "0 min" control, or treated with the CNR1 agonist WIN55,212-2 (1 mM) for 30 min or 60 min and then washed with calcium-free PBS (Sigma-Aldrich, D8537) to strip off the residual noninternalized M1 antibody (M1-FLAG binding is calcium-dependent).…”