Stangherlin, A. et al. (2011) cGMP signals modulate cAMP levels in a compartment-specific manner to regulate catecholamine-dependent signaling in cardiac myocytes. Circulation Research, 108 (8). pp. 929-939. ISSN 0009-7330 (doi:10.1161/CIRCRESAHA.110.230698)
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Publisher's URL: http://dx.doi.org/10.1161/CIRCRESAHA.110.230698
Rationale:cAMP and cGMP are intracellular second messengers involved in heart pathophysiology. cGMP can potentially affect cAMP signals via cGMP-regulated phosphodiesterases (PDEs).
Objective:To study the effect of cGMP signals on the local cAMP response to catecholamines in specific subcellular compartments.
Methods and Results:We used real-time FRET imaging of living rat ventriculocytes expressing targeted cAMP and cGMP biosensors to detect cyclic nucleotides levels in specific locales. We found that the compartmentalized, but not the global, cAMP response to isoproterenol is profoundly affected by cGMP signals. The effect of cGMP is to increase cAMP levels in the compartment where the protein kinase (PK)A-RI isoforms reside but to decrease cAMP in the compartment where the PKA-RII isoforms reside. These opposing effects are determined by the cGMP-regulated PDEs, namely PDE2 and PDE3, with the local activity of these PDEs being critically important. The cGMP-mediated modulation of cAMP also affects the phosphorylation of PKA targets and myocyte contractility.
Conclusions:cGMP signals exert opposing effects on local cAMP levels via different PDEs the activity of which is exerted in spatially distinct subcellular domains. Inhibition of PDE2 selectively abolishes the negative effects of cGMP on cAMP and may have therapeutic potential.
|Glasgow Author(s):||Smith, Prof Godfrey and Gesellchen, Dr Frank and Zaccolo, Prof Manuela and Stangherlin, Dr Alessandra and Berrera, Dr Marco and Surdo, Dr Nicoletta and Terrin, Ms Anna|
|Authors:||Stangherlin, A., Gesellchen, F., Zoccarato, A., Terrin, A., Fields, L.A., Berrera, M., Surdo, N.C., Craig, M.A., Smith, G.L., Hamilton, G., and Zaccolo, M.|
|College/School:||College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology|
|Journal Name:||Circulation Research|
|Publisher:||American Heart Association|
|Published Online:||17 February 2011|