Regulation of cAMP levels in area CA1 of hippocampus by G _i/o-coupled receptors is stimulus dependent in mice

The cAMP signaling cascade plays a critical role in regulating synaptic efficacy and cellular excitability in hippocampus. Adenylyl cyclase (AC) activation and subsequent generation of cAMP occurs through a number of mechanisms in area CA1 of hippocampus, including Gα _s-mediated stimulation upon G-protein coupled receptor (GPCR) activation and Ca ²⁺-mediated stimulation upon NMDA receptor activation. In addition, activation of G _i/o-coupled receptor subtypes can regulate cAMP levels through modulation of AC activity. Multiple G _i/o-coupled receptor subtypes are expressed in area CA1, where they are commonly thought to dampen synaptic transmission and excitability, in part through inhibition of AC activity and cAMP generation. However, a large family of ACs exists, and in recombinant systems, the cAMP signals generated by these AC isoforms are both inhibited and enhanced by G _i/o-coupled receptors in a manner dependent on the AC isoform and stimulus. Thus, we have assessed the effects of activating several different G _i/o-coupled receptors on the generation of cAMP induced either by NMDA receptor activation or by β-adrenergic receptor activation within area CA1 of mouse hippocampus. We find that in situ the effect of G _i/o-coupled receptor activation does indeed depend upon the means by which ACs are activated. In addition, the effects are also G _i/o-coupled receptor-specific, suggesting additional complexity. These data indicate that G _i/o-coupled receptors may play roles in "routing" second messenger signaling in area CA1.