Myosin phosphatase target subunit 1 (MYPT1) regulates the contraction and relaxation of vascular smooth muscle and maintains blood pressure

J Biol Chem. 2014 Aug 8;289(32):22512-23. doi: 10.1074/jbc.M113.525444. Epub 2014 Jun 20.

Abstract

Myosin light chain phosphatase with its regulatory subunit, myosin phosphatase target subunit 1 (MYPT1) modulates Ca(2+)-dependent phosphorylation of myosin light chain by myosin light chain kinase, which is essential for smooth muscle contraction. The role of MYPT1 in vascular smooth muscle was investigated in adult MYPT1 smooth muscle specific knock-out mice. MYPT1 deletion enhanced phosphorylation of myosin regulatory light chain and contractile force in isolated mesenteric arteries treated with KCl and various vascular agonists. The contractile responses of arteries from knock-out mice to norepinephrine were inhibited by Rho-associated kinase (ROCK) and protein kinase C inhibitors and were associated with inhibition of phosphorylation of the myosin light chain phosphatase inhibitor CPI-17. Additionally, stimulation of the NO/cGMP/protein kinase G (PKG) signaling pathway still resulted in relaxation of MYPT1-deficient mesenteric arteries, indicating phosphorylation of MYPT1 by PKG is not a major contributor to the relaxation response. Thus, MYPT1 enhances myosin light chain phosphatase activity sufficient for blood pressure maintenance. Rho-associated kinase phosphorylation of CPI-17 plays a significant role in enhancing vascular contractile responses, whereas phosphorylation of MYPT1 in the NO/cGMP/PKG signaling module is not necessary for relaxation.

Keywords: Contractile Protein; Myosin; Myosin Light Chain Phosphatase, Myosin Phosphorylation, Vascular Smooth Muscle; Phosphatase; Smooth Muscle; Vascular Biology.

Publication types

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

MeSH terms

  • Animals
  • Blood Pressure / physiology
  • Female
  • Hypertension / etiology
  • Hypertension / physiopathology
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mesenteric Arteries / physiology
  • Mice
  • Mice, Knockout
  • Muscle Proteins / metabolism
  • Muscle, Smooth, Vascular / physiology*
  • Myosin Light Chains / metabolism
  • Myosin-Light-Chain Kinase / deficiency
  • Myosin-Light-Chain Kinase / genetics
  • Myosin-Light-Chain Kinase / physiology*
  • Myosin-Light-Chain Phosphatase
  • Nitric Oxide / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Signal Transduction
  • Vasoconstriction / physiology
  • Vasodilation / physiology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • Myosin Light Chains
  • Phosphoproteins
  • Ppp1r14a protein, mouse
  • Nitric Oxide
  • Myosin-Light-Chain Kinase
  • Myosin-Light-Chain Phosphatase
  • Ppp1r12a protein, mouse