Constitutive Gi2-dependent Activation of Adenylyl Cyclase Type II by the 5-HT1A Receptor
Journal of Biological Chemistry
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
... r and ACII plasmids, 5-HT1A agonists induced a 1.5-fold increase in cAMP level. Cotransfection of 5-HT1A receptor, ACII, and G␣ i2 , but not G␣ i1 , G␣ i3 , or G␣ o , resulted in an agonist-independent 6-fold increase in the basal cAMP level, suggesting that G i2 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␤␥ antagonist, ␤CT, suggesting an important role for G␤␥mediated activation of ACII. The Thr-149 3 Ala mutation in the second intracellular domain of the 5-HT1A receptor disrupted G␤␥-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.