A GIPC1-Palmitate Switch Modulates Dopamine Drd3 Receptor Trafficking and Signaling

Abstract

f Palmitoylation is involved in several neuropsychiatric and movement disorders for which a dysfunctional signaling of the dopamine D3 receptor (Drd3) is hypothesized. Computational modeling of Drd3's homologue, Drd2, has shed some light on the putative role of palmitoylation as a reversible switch for dopaminergic receptor signaling. Drd3 is presumed to be palmitoylated, based on sequence homology with Drd2, but the functional attributes afforded by Drd3 palmitoylation have not been studied. Since these receptors are major targets of antipsychotic and anti-Parkinsonian drugs, a better characterization of Drd3 signaling and posttranslational modifications, like palmitoylation, may improve the prospects for drug development. Using molecular dynamics simulations, we evaluated in silico how Drd3 palmitoylation could elicit significant remodeling of the C-terminal cytoplasmic domain to expose docking sites for signaling proteins. We tested this model in cellulo by using the interaction of Drd3 with the G-alpha interacting protein (GAIP) C terminus 1 (GIPC1) as a template. From a series of biochemical studies, live imaging, and analyses of mutant proteins, we propose that Drd3 palmitoylation acts as a molecular switch for Drd3-biased signaling via a GIPC1-dependent route, which is likely to affect the mode of action of antipsychotic drugs.

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…Palmitoylation at the C-terminus of the DR protein has been documented for D1, D2, and D3 receptors as reversible switch for DR signaling via the cAMP path ( Ebersole et al., 2015 ; Arango-Lievano et al., 2016 ). The most important posttranscriptional modification of D2 and D3 receptors is the N-linked glycosylation that classically affects both correct cell surface expression and signaling/internalization (caveolin - chlatrin mediated) ( Min et al., 2015 ).…”

“…Palmitoylation at the C-terminus of the DR protein has been documented for D1, D2, and D3 receptors as reversible switch for DR signaling via the cAMP path (Ebersole et al, 2015;Arango-Lievano et al, 2016). The most important FIGURE 1 | Simplified sketch of the dopamine receptors (DR) connectome in the basal ganglia/striatum with a zoom (right circle) on signal transduction at presynaptic level in medium spiny neurons (MSN) dendritic boutons.…”

Channelrhodopsin-2 Function is Modulated by Residual Hydrophobic Mismatch with the Surrounding Lipid Environment

“…The simulations were carried out in a generic model of the membrane environment of POPC lipids to enable the evaluation of results in the context of the overwhelming majority of studies of membrane proteins and GPCRs in particular, using this model membrane. These include computational studies by us [19,[53][54][55] and many others [56]. The expectation that membrane-determined effects will result from RHM for the ChR was confirmed by the computational results and the corresponding experimental probing.…”

GIPC proteins negatively modulate Plexind1 signaling during vascular development

“…GIPCs limit or promote the activity of their transmembrane consorts by regulating their surface expression, G-protein signaling, and vesicular trafficking (Lanahan et al, 2010; De Vries et al, 1998a; Naccache et al, 2006; Reed et al, 2005; Giese et al, 2012; Lou et al, 2001; Bunn et al, 1999; Wieman et al, 2009; Blobe et al, 2001; Chak and Kolodkin, 2014; Hu et al, 2003; Booth et al, 2002; Jeanneteau et al, 2004a; Arango-Lievano et al, 2016; Varsano et al, 2012). Whether GIPC binding limits, versus enables, PLXND1 signaling gives different predictions regarding the nature of the plxnd1 skt6 allele, which can be assessed by its ability to complement the plxnd1 fov01b null mutation, the vascular phenotype of plxnd1 skt6 homozygotes and their sensitivity to antiangiogenic compounds.…”

“…This residue plugs into a hydrophobic GIPC pocket between the GH1 and PDZ domains (Gay et al, 2011; Shang et al, 2017). On the other hand, some type I transmembrane proteins, including Plxns, are S-palmitoylated (Holland and Thomas, 2017; Blaskovic et al, 2013), and S-palmitoylation of the carboxy tail of the GIPC1-binding dopamine Drd3 receptor buries the PBM within the cell membrane to prevent the Drd3-GIPC1 interaction (Arango-Lievano et al, 2016).…”