Differential coupling of serotonin 5-HT1A and 5-HT1B receptors to activation of ERK2 and inhibition of adenylyl cyclase in transfected CHO cells

Although the subtypes of serotonin 5-HT1 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 coupl ing of 5-HT1A and 5-HT1B receptors to adenylyl cyclase and to the mitogen-a ctivated protein kinase ERK2 (extracellular signal-regulated kinase-2). We found that 5-HT1B receptors couple better to activation of ERK2 and inhibit ion of adenylyl cyclase than do 5-HT1A receptors. 5-HT stimulated a maximal fourfold increase in ERK2 activity in nontransfected cells that express en dogenous 5-HT1B receptors at a very low density and a maximal 13-fold incre ase in transfected cells expressing 230 fmol of 5-HT1B receptor/mg of membr ane protein. In contrast, activation of 5-HT1A receptors stimulated only a 2.8-fold maximal activation of ERK2 in transfected cells expressing recepto rs 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 prot ein. Similarly, 5-HT1A, but not 5-HT1B, receptors were found to cause signi ficant inhibition of forskolin-stimulated cyclic AMP accumulation only when expressed at high densities. These findings demonstrate that although both 5-HT1A and 5-HT1B receptors have been shown to couple to G proteins of the G(i) class, they exhibit differences in coupling to ERK2 and adenylyl cycl ase.