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 intracellul ar Ca2+ to cAMP increases. Since optimal cAMP levels may be crucial fo r some types of synaptic plasticity, mechanisms for inhibition of Ca2-stimulated adenylyl cyclases may also be important for neuroplasticit y. Here we report that Ca2+ stimulation of I-AC is inhibited by activa tion of G(i)-coupled somatostatin and dopamine D(2)L receptors. This i nhibition is due primarily to G(i alpha) and not beta gamma subunits s ince coexpression of beta gamma-binding proteins with I-AC did not aff ect somatostatin inhibition. However, beta gamma released from G(s) di d inhibit I-AC, indicating that the enzyme can be inhibited by beta ga mma in vivo. Interestingly, type VIII adenylyl cyclase (VIII-AC), anot her Ca2+-stimulated adenylyl cyclase, was not inhibited by G(i)-couple d receptors. These data indicate that I-AC and VIII-AC are differentia lly regulated by G(i)-coupled receptors and provide distinct mechanism s for interactions between the Ca2+ and cAMP signal transduction syste ms. We propose that I-AC may be particularly important for synaptic pl asticity that depends upon rapid and transient cAMP increases, whereas VIII-AC may contribute to transcriptional-dependent synaptic plastici ty that is dependent upon prolonged, Ca2+-stimulated cAMP increases.