Differential regulation of type I and type VIII Ca2+-stimulated adenylyl cyclases by G(i)-coupled receptors in vivo

Coupling of intracellular Ca2+ to cAMP increases may be important for some forms of synaptic plasticity. The type I adenylyl cyclase (I-AC) is a neural-specific, Ca2+. stimulated enzyme that couples intracellular Ca2+ to cAMP increases. Since optimal cAMP levels may be crucial for some types of synaptic plasticity, mechanisms for inhibition of Ca2+-stimulated adenylyl cyclases may also be important for neuroplasticity. Here we report that Ca2+ stimulation of I-AC is inhibited by activation of G(i)-coupled somatostatin and dopamine D(2)L receptors. This inhibition is due primarily to G(i alpha) and not beta gamma subunits since coexpression of beta gamma-binding proteins with I-AC did not affect somatostatin inhibition. However, beta gamma released from G(s) did inhibit I-AC, indicating that the enzyme can be inhibited by beta gamma in vivo. Interestingly, type VIII adenylyl cyclase (VIII-AC), another Ca2+-stimulated adenylyl cyclase, was not inhibited by G(i)-coupled receptors. These data indicate that I-AC and VIII-AC are differentially regulated by G(i)-coupled receptors and provide distinct mechanisms for interactions between the Ca2+ and cAMP signal transduction systems. We propose that I-AC may be particularly important for synaptic plasticity that depends upon rapid and transient cAMP increases, whereas VIII-AC may contribute to transcriptional-dependent synaptic plasticity that is dependent upon prolonged, Ca2+-stimulated cAMP increases.