title: Synthetic Peptides as cGMP-Independent Activators of cGMP-Dependent Protein Kinase Iα.
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.
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Moon
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Tykocki
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Sheehe
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA.
authors.forename: Brent W
authors.initials: BW
authors.lastname: Osborne
authors.affiliation: Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), Inhoffenstraße 7, 38124 Braunschweig, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Tegge
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Brayden
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Vermont, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: wolfgang.dostmann@uvm.edu.
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Dostmann
mesh_terms: D000818:Animals; D002942:Circular Dichroism; D006152:Cyclic GMP; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000302:isolation & purification / Q000378:metabolism*; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000138:chemical synthesis / Q000494:pharmacology; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D020033:Protein Isoforms / Q000302:isolation & purification; D051381:Rats
chemical_list: D020536:Enzyme Activators; D019151:Peptide Library; D010455:Peptides; D020033:Protein Isoforms; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D006152:Cyclic GMP