Angiotensin II Enhances Adenylyl Cyclase Signaling via Ca2+/Calmodulin. Gq-Gs Cross-Talk Regulates Collagen Production in Cardiac Fibroblasts

Authors

Rennolds S. Ostrom, Chapman UniversityFollow
Jennifer E. Naugle, University of California, San Diego
Miki Hase, University of California, San Diego
Caroline Gregorian, University of California, San Diego
James S. Swaney, University of California, San Diego
Paul A. Insel, University of California, San Diego
Laurence L. Brunton, University of California, San Diego
J. Gary Meszaros, Northeastern Ohio Universities

Document Type

Article

Publication Date

2003

Abstract

Cardiac fibroblasts regulate formation of extracellular matrix in the heart, playing key roles in cardiac remodeling and hypertrophy. In this study, we sought to characterize cross-talk between Gq and Gs signaling pathways and its impact on modulating collagen synthesis by cardiac fibroblasts. Angiotensin II (ANG II) activates cell proliferation and collagen synthesis but also potentiates cyclic AMP (cAMP) production stimulated by β-adrenergic receptors (β-AR). The potentiation of β-AR-stimulated cAMP production by ANG II is reduced by phospholipase C inhibition and enhanced by overexpression of Gq. Ionomycin and thapsigargin increased intracellular Ca2+ levels and potentiated isoproterenol- and forskolin-stimulated cAMP production, whereas chelation of Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N′, N′-tetraacetic acid/AM inhibited such potentiation. Inhibitors of tyrosine kinases, protein kinase C, or Gβγ did not alter this cross-talk. Immunoblot analyses showed prominent expression of adenylyl cyclase 3 (AC3), a Ca2+-activated isoform, along with AC2, AC4, AC5, AC6, and AC7. Of those isoforms, only AC3 and AC5/6 proteins were detected in caveolin-rich fractions. Overexpression of AC6 increased βAR-stimulated cAMP accumulation but did not alter the size of the ANG II potentiation, suggesting that the cross-talk is AC isoform-specific. Isoproterenol-mediated inhibition of serum-stimulated collagen synthesis increased from 31 to 48% in the presence of ANG II, indicating that βAR-regulated collagen synthesis increased in the presence of ANG II. These data indicate that ANG II potentiates cAMP formation via Ca2+-dependent activation of AC activity, which in turn attenuates collagen synthesis and demonstrates one functional consequence of cross-talk between Gq and Gs signaling pathways in cardiac fibroblasts.

Comments

This article was originally published in Journal of Biological Chemistry, volume 278, issue 27, in 2003. DOI: 10.1074/jbc.M212659200

Recommended Citation

Rennolds S Ostrom, Jennifer E. Naugle, Miki Hase, Caroline Gregorian, James S. Swaney, Paul A. Insel, Laurence L. Brunton and J. Gary Meszaros. Angiotensin II enhances adenylyl cyclase signaling via Ca2+/calmodulin. Gq-Gs cross-talk regulates collagen production in cardiac fibroblasts. J Biol Chem, 278(27):24461-8, 2003.

Copyright

American Society for Biochemistry and Molecular Biology