Alterations in 5-HT 2A receptor signaling in male and female transgenic rats over-expressing either Gq or RGS-insensitive Gq protein

Abstract

Serotonin 2A (5-HT 2A) receptors are coupled to G αq and G α11 proteins to activate phospholipase C (PLC). Regulators of G-protein signaling proteins (RGS) modulate G-protein signaling by accelerating the intrinsic GTPase activity of G αq and G α11. This study investigated the effects of over-expression of wild-type G αq proteins (Gq-Tg) and over-expression of RGS-insensitive G αq proteins (G188S, RGSi-Tg) on 5-HT 2A receptor mediated signaling in transgenic rats. Over-expression of wild-type G αq and RGS insensitive mutant G αq did not produce significant alterations in the levels of G α11, RGS2, RGS4, RGS7, RGS16 or 5-HT 2A proteins. RGSi-Tg rats had higher oxytocin and corticosterone responses to (−)DOI, a 5-HT 2A/2C receptor agonist, compared to Gq-Tg rats. RGSi-Tg and Gq-Tg rats had higher ACTH responses to (−)DOI compared to control rats. Similarly, 5-HT-stimulated PLC activity in the frontal cortex was higher in RGSi-Tg and Gq-Tg rats compared to control rats. In contrast, GTPγS-stimulated PLC activity was higher in Gq-Tg rats but not in RGSi-Tg rats compared to control rats. There was a small but statistically significant increase in the affinity of [ 125I]-DOI labeled 5-HT 2A receptors in RGSi-Tg rats and Gq-Tg rats compared to controls. There were no significant differences in B max and K d of [ 3H] ketanserin labeled 5-HT 2A receptors among the three groups. These data suggest that the effect of RGS proteins on 5-HT 2A receptor signaling is cell type specific. In transgenic rats over-expressing G αq, endogenous RGS proteins have a negative effect on 5-HT 2A receptor-mediated oxytocin release. In contrast, endogenous RGS protein had no impact on 5-HT 2A receptor-mediated ACTH release in transgenic rats.