Gα _q -coupled receptors activate cAMP signaling through Ca ²⁺ /calmodulin-stimulated adenylyl cyclases

Among the various G protein–mediated intracellular signaling pathways activated by G protein–coupled receptors (GPCRs), Gα _s and Gα _i stimulate and inhibit adenylyl cyclases (ADCYs), leading to increases and decreases in cAMP abundance, respectively. Here, we investigated the contribution of Gα _q -coupled receptors (Gα _q -GPCRs), which typically activate phospholipase C (PLC) and stimulate intracellular Ca ²⁺ generation, to the regulation of cAMP signaling. We activated the endogenous Gα _q -coupled muscarinic acetylcholine receptors (Gα _q -mAChRs) and the group 1 metabotropic glutamate receptors (mGluR1/5) in ex vivo hippocampal slices from mice. We also used a chemogenetics approach to activate Gα _q -DREADDs (designer receptors exclusively activated by designer drugs) through hM3Dq. We found that stimulation of these Gα _q -GPCRs not only increased the abundance of cAMP but also activated downstream, cAMP-mediated intracellular signaling pathways. This GPCR-dependent cAMP signaling required both Gα _q activity and intracellular Ca ²⁺ . Additionally, hippocampal slices from mice lacking the Ca ²⁺ /calmodulin-stimulated ADCYs, ADCY1 and ADCY8, did not exhibit Gα _q -GPCR–mediated cAMP signaling and showed impaired synaptic long-term depression (LTD) mediated by Gα _q -mAChRs. Together, our findings highlight a nonconventional function of Gα _q -GPCRs in regulating cAMP signaling through distinct ADCYs.