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(Circulation Research. 2006;98:1159.)
© 2006 American Heart Association, Inc.

Cellular Biology

Urocortin-Induced Decrease in Ca²⁺ Sensitivity of Contraction in Mouse Tail Arteries Is Attributable to cAMP-Dependent Dephosphorylation of MYPT1 and Activation of Myosin Light Chain Phosphatase

Lubomir T. Lubomirov, Katrin Reimann, Doris Metzler, Veronika Hasse, Robert Stehle, Masaaki Ito, David J. Hartshorne, Hristo Gagov, Gabriele Pfitzer, Rudolf Schubert

From the Institute of Vegetative Physiology (L.T.L., K.R., D.M., V.H., R. Stehle, G.P.), University of Cologne, Germany; First Department of Internal Medicine (M.I.), Mie University School of Medicine, Japan; Muscle Biology Group (D.J.H.), University of Arizona, Tucson; Department of Physiology (H.G.), St. Kliment Ohridski University, Sofia, Bulgaria; and Institute of Physiology (R. Schubert), University of Rostock, Germany.

Correspondence to Lubomir T. Lubomirov, Institute of Vegetative Physiology, University Koeln, Robert-Koch-Str. 39, 50931 Köln, Germany. E-mail lubomir.lubomirov{at}uni-koeln.de

Urocortin, a vasodilatory peptide related to corticotropin-releasing factor, may be an endogenous regulator of blood pressure. In vitro, rat tail arteries are relaxed by urocortin by a cAMP-mediated decrease in myofilament Ca²⁺ sensitivity through a still unclear mechanism. Here we show that contraction of intact mouse tail arteries induced with 42 mmol/L KCl or 0.5 µmol/L noradrenaline was associated with a 2-fold increase in the phosphorylation of the regulatory subunit of myosin phosphatase (SMPP-1M), MYPT1, at Thr696, which was reversed in arteries relaxed with urocortin. Submaximally (pCa 6.1) contracted mouse tail arteries permeabilized with -toxin were relaxed with urocortin by 39±3% at constant [Ca²⁺], which was associated with a decrease in myosin light chain (MLC₂₀^Ser19), MYPT1^Thr696, and MYPT1^Thr850 phosphorylation by 60%, 28%, and 52%, respectively. The Rho-associated kinase (ROK) inhibitor Y-27632 decreased MYPT1 phosphorylation by a similar extent. Inhibition of PP-2A with 3 nmol/L okadaic acid had no effect on MYPT1 phosphorylation, whereas inhibition of PP-1 with 3 µmol/L okadaic acid prevented dephosphorylation. Urocortin increased the rate of dephosphorylation of MLC₂₀^Ser19 2.2-fold but had no effect on the rate of contraction under conditions of, respectively, inhibited kinase and phosphatase activities. The effect of urocortin on MLC₂₀^Ser19 and MYPT1 phosphorylation was blocked by Rp-8-CPT-cAMPS and mimicked by Sp-5,6-DCl-cBIMPS. In summary, these results provide evidence that Ca²⁺-independent relaxation by urocortin can be attributed to a cAMP-mediated increased activity of SMPP-1M which at least in part is attributable to a decrease in the inhibitory phosphorylation of MYPT1.

Key Words: arteries • calcium sensitivity • urocortin • PKA • myosin phosphatase

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