Synergistic activation of the type I adenylyl cyclase by Ca2+ and G(s)- coupled receptors in vivo

G. A. Wayman, S. Impey, Z. Wu, W. Kindsvogel, L. Prichard, D. R. Storm

Research output: Contribution to journalArticle

104 Scopus citations

Abstract

The type I adenylyl cyclase is directly stimulated by Ca2+ and calmodulin in vivo (Choi, E. J., Wong, S. T., Hinds, T. R. and Storm, D. R. (1992) J. Biol. Chem. 267, 12440-12442; Wu, Z., Wong, S. T., and Storm, D. R. (1993) J. Biol. Chem. 268, 23766-23768). In this study, we examined the sensitivity of the type I adenylyl cyclase expressed in HEK-293 cells to β- adrenergic agonists or glucagon when intracellular Ca2+ was elevated by Ca2+ ionophore or carbachol. Although previous studies have shown that this enzyme can be directly stimulated by activated G(s) in vitro, we demonstrate that it is not stimulated by G(s)-coupled receptors in vivo. However, the enzyme was stimulated by G(s)-coupled receptors in vivo when it was activated by intracellular Ca2+. For example, the Ca2+ ionophore A23187 stimulated the enzyme 3 ± 0.5-fold (n = 9) and isoproterenol alone did not stimulate the enzyme, but the combination of the two stimulated type I adenylyl cyclase 13 ± 2-fold (n = 9) in vivo. Similarly, 500 nM glucagon alone did not stimulate the enzyme but the combination of A23187 and glucagon activated the enzyme 90 ± 8-fold (n = 4). Synergistic stimulation of type I adenylyl cyclase activity was also obtained with combinations of carbachol and isoproterenol or glucagon. This phenomenon was not observed with a mutant enzyme that is insensitive to Ca2+ and calmodulin, suggesting that conformational changes caused by binding of calmodulin to the type I adenylyl cyclase enhance binding or coupling to activated G(s). These data illustrate that this adenylyl cyclase can couple Ca2+ and neurotransmitter signals to generate optimal cAMP levels, a property of the enzyme that may be important for its role in learning and memory in mammals.

Original languageEnglish (US)
Pages (from-to)25400-25405
Number of pages6
JournalJournal of Biological Chemistry
Volume269
Issue number41
StatePublished - Jan 1 1994

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Wayman, G. A., Impey, S., Wu, Z., Kindsvogel, W., Prichard, L., & Storm, D. R. (1994). Synergistic activation of the type I adenylyl cyclase by Ca2+ and G(s)- coupled receptors in vivo. Journal of Biological Chemistry, 269(41), 25400-25405.