Differential regulation of type I and type VIII Ca2+-stimulated adenylyl cyclases by Gi-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 Gi-coupled somatostatin and dopamine D2L receptors. This inhibition is due primarily to Gialpha and not betagamma subunits since coexpression of betagamma-binding proteins with I-AC did not affect somatostatin inhibition. However, betagamma released from Gs did inhibit I-AC, indicating that the enzyme can be inhibited by betagamma in vivo. Interestingly, type VIII adenylyl cyclase (VIII-AC), another Ca2+-stimulated adenylyl cyclase, was not inhibited by Gi-coupled receptors. These data indicate that I-AC and VIII-AC are differentially regulated by Gi-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.
Nielsen
M D
MD
Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
Chan
G C
GC
Poser
S W
SW
Storm
D R
DR
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D013004:Somatostatin / Q000494:pharmacology; D015293:Transducin / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010566:Virulence Factors, Bordetella; D000001:Calcimycin; D013004:Somatostatin; D002217:Carbachol; D000242:Cyclic AMP; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D015293:Transducin; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1; D007545:Isoproterenol; D002118:Calcium; D004298:Dopamine