Abstract:Although the subtypes of serotonin 5-HT 1 receptors have distinct structure and pharmacology, it has not been clear if they also exhibit differences in coupling to cellular signals. We have sought to compare directly the coupling of 5-HT 1A and 5-HT 1B receptors to adenylyl cyclase and to the mitogen-activated protein kinase ERK2 (extracellular signal-regulated kinase-2). We found that 5-HT 1B receptors couple better to activation of ERK2 and inhibition of adenylyl cyclase than do 5-HT 1A receptors. 5-HT stimulated a maximal fourfold increase in ERK2 activity in nontransfected cells that express endogenous 5-HT 1B receptors at a very low density and a maximal 13-fold increase in transfected cells expressing 230 fmol of 5-HT 1B receptor/mg of membrane protein. In contrast, activation of 5-HT 1A receptors stimulated only a 2.8-fold maximal activation of ERK2 in transfected cells expressing receptors at 300 fmol/mg of membrane protein but did stimulate a 12-fold increase in activity in cells expressing receptors at 3,000 fmol/mg of membrane protein. Similarly, 5-HT 1A , but not 5-HT 1B , receptors were found to cause significant inhibition of forskolin-stimulated cyclic AMP accumulation only when expressed at high densities. These findings demonstrate that although both 5-HT 1A and 5-HT 1B receptors have been shown to couple to G proteins of the G i class, they exhibit differences in coupling to ERK2 and adenylyl cyclase. Key Words: Extracellular signal-regulated kinase-2-Mitogen-activated protein kinase -Cyclic AMP-5-HT 1A receptors-5-HT 1B receptors-Serotonin.