Journal
CHEMISTRY & BIOLOGY
Volume 22, Issue 12, Pages 1653-1661Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2015.11.005
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Funding
- National Institutes of Health (NIH) [5T32 HL007647, 1K01 DK103840, P01 HL095488, R01 HL68891]
- Totman Trust for Biomedical Research
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PKG is a multifaceted signaling molecule and potential pharmaceutical target due to its role in smooth muscle function. A helix identified in the structure of the regulatory domain of PKG I alpha suggests a novel architecture of the holoenzyme. In this study, a set of synthetic peptides (S-tides), derived from this helix, was found to bind to and activate PKG I alpha in a cyclic guanosine monophosphate (cGMP)-independent manner. The most potent S-tide derivative (S1.5) increased the open probability of the potassium channel K(Ca)1.1 to levels equivalent to saturating cGMP. Introduction of S1.5 to smooth muscle cells in isolated, endothelium-denuded cerebral arteries through a modified reversible permeabilization procedure inhibited myogenic constriction. In contrast, in endothelium-intact vessels S1.5 had no effect on myogenic tone. This suggests that PKG Ia activation by S1.5 in vascular smooth muscle would be sufficient to inhibit augmented arterial contractility that frequently occurs following endothelial damage associated with cardiovascular disease.
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