Membrane Receptors & Signal Transduction I
2/3/2013 1:45:00 PM
FUNCTIONAL SIGNALING CHANGES RESULTING FROM GPCR HETEROMERIZATION: RELEVANCE TO PSYCHOSIS
, Diomedes E. Logothetis.
Virginia Commonwealth University, Richmond, VA, USA.
Functional Signaling Changes Resulting from GPCR Heteromerization: Relevance to Psychosis
A broad spectrum of symptoms has been evidenced in psychotic disorders, while nearly 70 years of research has produced anti-psychotic drugs (APDs) that alleviate only certain ones of these symptoms and may cause the manifestation of debilitating side effects. G-protein coupled receptors (GPCRs) have emerged as the predominant pharmaceutical target, and a specific GPCR is integral to each of three neurotransmitter pathways: the dopamine 2 receptor (D2R) in the dopaminergic system, the serotonin 2A receptor (5HT2AR) in the serotonergic system, and the metabotropic glutamate 2 receptor (mGluR2) in the glutamatergic system. While all three GPCRs form homomers, heteromers of 5HT2AR have also been shown to form with D2R or with mGluR2. Our group has shown that heteromerization enhances the Gi activity of mGluR2, while it decreases the Gq activity of 5HT2AR. Application of ligands to one side of the mGluR2-5HT2AR revealed inverse cross-signaling. Thus APDs, inverse agonists of 5HT2AR or agonists of mGluR2, aimed to restore high Gi over Gq signaling (Fribourg et al., 2011). Upon D2R-5HT2AR formation, the Gq activity of the 5HT2AR increased by approximately 60% and decreased when an agonist was applied to D2R. These results lead us to hypothesize that the inverse signaling coupling also exists in the D2R/5HT2AR heteromeric complex. We are in the process of examining the influence of 5HT2AR on Gi signaling through D2R. The lack of current clinical success pertaining to the use of APDs may be a direct reflection of the complex relationship between D2R, mGluR2, and 5HT2AR. A better understanding of the interrelationship of these three GPCRs may lead to better management of symptoms involved in psychotic disorders.
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