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

Chem Biol. 2015 Dec 17;22(12):1653-61. doi: 10.1016/j.chembiol.2015.11.005.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Circular Dichroism
  • Cyclic GMP*
  • Cyclic GMP-Dependent Protein Kinase Type I / isolation & purification
  • Cyclic GMP-Dependent Protein Kinase Type I / metabolism*
  • Drug Design*
  • Enzyme Activation / drug effects
  • Enzyme Activators / chemical synthesis
  • Enzyme Activators / pharmacology
  • Microscopy, Confocal
  • Muscle, Smooth, Vascular / drug effects
  • Peptide Library*
  • Peptides / chemical synthesis
  • Peptides / pharmacology*
  • Protein Isoforms / isolation & purification
  • Rats

Substances

  • Enzyme Activators
  • Peptide Library
  • Peptides
  • Protein Isoforms
  • Cyclic GMP-Dependent Protein Kinase Type I
  • Cyclic GMP