Synthetic Peptides as cGMP-Independent Activators of cGMP-Dependent Protein Kinase Iα

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 Iα 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 Iα in a cyclic guanosine monophosphate (cGMP)-independent manner. The most potent S-tide derivative (S1.5) increased the open probability of the potassium channel KCa1.1 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 Iα 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. [Display omitted] •S-tides are a new class of molecule capable of selectively activating PKG Iα•S-tides target PKG Iα and elevate the open probability of K+ channels (BK, KCa1.1)•S-tides modulate vascular contractility via PKG Iα effects on BK channels•S-tides dilate endothelium-denuded arteries that have exaggerated myogenic tone The control of vascular smooth muscle relaxation and blood flow are tightly linked to the activity of cGMP-dependent protein kinase (PKG). Moon et al. demonstrate the development and assay of a class of novel vasodilators that are selective cGMP-independent PKG Iα activators.