Abstract
The G-protein linked signaling system (GPLS) comprises a large number of G-proteins, G protein-coupled receptors (GPCRs), GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP), phosphatidylinositols, and ion channels. The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD) and bipolar disorder (BPD). This study evaluated whether GPLS is altered at the transcript level. The gene expression in the dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) were compared from MDD, BPD, and control subjects using Affymetrix Gene Chips and real time quantitative PCR. High quality brain tissue was used in the study to control for confounding effects of agonal events, tissue pH, RNA integrity, gender, and age. GPLS signaling transcripts were altered especially in the ACC of BPD and MDD subjects. Transcript levels of molecules which repress cAMP activity were increased in BPD and decreased in MDD. Two orphan GPCRs, GPRC5B and GPR37, showed significantly decreased expression levels in MDD, and significantly increased expression levels in BPD. Our results suggest opposite changes in BPD and MDD in the GPLS, “activated” cAMP signaling activity in BPD and “blunted” cAMP signaling activity in MDD. GPRC5B and GPR37 both appear to have behavioral effects, and are also candidate genes for neurodegenerative disorders. In the context of the opposite changes observed in BPD and MDD, these GPCRs warrant further study of their brain effects.
Highlights
The G-protein linked signaling system (GPLS) comprises Gproteins, G protein-coupled receptors (GPCRs), G-protein coupled receptor (GPCR) ligands, and downstream effector molecules
The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD) and bipolar disorder (BPD)
There was a nominal enrichment of genes that act negatively on cyclic adenosine monophosphate (cAMP) signaling activity (Gi proteins, phosphodiesterase, protein kinase A inhibitors, and protein phosphatase) in BPD in the anterior cingulate cortex (ACC)
Summary
The G-protein linked signaling system (GPLS) comprises Gproteins, G protein-coupled receptors (GPCRs), GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP), phosphatidylinositols, and ion channels. GPCRs can signal ligand binding events by conformational changes that activate intracellular G proteins. Active G proteins in turn trigger intracellular downstream signaling pathways. Evidence suggests that altered GPCRs and their two major downstream signaling pathways, mediated by effectors such as cAMP and phosphatidylinositol, may be involved in the pathophysiology of BPD and MDD as well as in the mechanism of drug treatment for these disorders. Altered immunoreactivities and functional activities of proteins related to cAMP signaling pathways have been reported in the brain and peripheral blood cells of BPD patients (Jope et al, 1996; Karege et al, 1996; Gould and Manji, 2002; Chang et al, 2003). There are 150 orphan GPCRs, with no known ligand or function (Wise et al, 2004), that might be relevant to downstream signaling dysregulation observed in www.frontiersin.org
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