Constitutive Gi2-dependent activation of adenylyl cyclase type II by the 5-HT1A receptor -: Inhibition by anxiolytic partial agonists

The 5-HT1A receptor is implicated in depression and anxiety. This receptor couples to G(i) proteins to inhibit adenylyl cyclase (AC) activity but can stimulate AC in tissues (e,g, hippocampus) that express ACII, The role of ACII in receptor-mediated stimulation of cAMP formation was examined in HEK-293 cells transfected with the 5-HT1A receptor, which mediated inhibition of basal and G(s)-induced cAMP formation in the absence of ACII, In cells cotransfected with 5-HT1A receptor and ACII plasmids, 5-HT1A agonists induced a 1.5-fold increase in cAMP level, Cotransfection of 5-HT1A receptor, ACII, and G alpha(i2), but not G alpha(i1), G alpha(i3), or G alpha(o), resulted in an agonist-independent B-fold increase in the basal cAMP level, suggesting that Gi, preferentially coupled the receptor to ACII, The 5-HT1B receptor also constitutively activated ACII, Constitutive activity of the 5-HT1A receptor was blocked by pertussis toxin and the G beta gamma antagonist, PCT, suggesting an important role for G beta gamma-mediated activation of ACII. The Thr-149 --> Ala mutation in the second intracellular domain of the 5-HT1A receptor disrupted G beta gamma-selective activation of ACII, Spontaneous 5-HT1A receptor activity was partially attenuated by 5-HT1A receptor partial agonists with anxiolytic activity (e,g, buspirone and flesinoxan) but was not altered by full agonists or antagonists. Thus, anxiolytic activity may involve inhibition of spontaneous 5-HT1A receptor activity.