Heterologous desensitization is evoked by both agonist and antagonist stimulation of the human 5-HT7 serotonin receptor

Previously, we demonstrated that human serotonin (5-HT) 5-HT7 receptors display marked constitutive activity. Here, we tested if the constitutive activation of adenylyl cyclase by 5-HT7 receptors influenced both the desensitization properties of transfected 5-HT7 receptors and the ability of endogenous Gs-coupled receptors to activate adenylyl cyclase. Using membranes from stably transfected HEK293 cells expressing the recombinant human 5-HT7 receptor splice variants (5-HT7(a), 5-HT7(b) and 5-HT7(d)), we compared the effects of 1-h or 24-h preincubation of the agonist 5-HT, partial inverse agonists mesulergine and SB269970, and full inverse agonists clozapine and methiothepin on subsequent activation of adenylyl cyclase by both 5-HT through transfected 5-HT7 receptors and the endogenous Gs-coupled β-adrenoceptors and prostaglandin receptors of HEK293 cells. The data show that stable expression of 5-HT7 receptors is sufficient to attenuate adenylyl cyclase activation by endogenous Gs-coupled receptors. Interestingly, preincubation with inverse agonists not only failed to result in the predicted resensitization of all receptor mediated adenylyl cyclase activation, but some inverse agonists further attenuated (desensitized) β-adrenoceptor and prostaglandin-stimulated adenylyl cyclase activation similar to long-term agonist exposure by 5-HT. These effects were not correlated with inverse agonist efficacy, were not accompanied by receptor down-regulation and appear to be mediated by a protein kinase A (PKA) independent mechanism. It is concluded that the human 5-HT7 receptor mediates heterologous desensitization of endogenous Gs-coupled receptors through an unknown and potentially novel mechanism.