Staurosporine inhibition of zipper-interacting protein kinase contractile effects in gastrointestinal smooth muscle

Author:

Borman Meredith A.12,MacDonald Justin A.12,Haystead Timothy A. J.12

Affiliation:

1. Smooth Muscle Research Group and Department of Biochemistry & Molecular Biology, University of Calgary, Calgary, AB T2N 4N1, Canada.

2. Department of Pharmacology and Cancer Biology, Duke University Medical Center, P.O. Box 3813, Durham, NC 27710, USA.

Abstract

Zipper-interacting protein kinase (ZIPK) is a serine–threonine kinase that has been implicated in Ca2+-independent myosin II phosphorylation and contractile force generation in vascular smooth muscle. However, relatively little is known about the contribution of this kinase to gastrointestinal smooth muscle contraction. The addition of a recombinant version of ZIPK that lacked the leucine zipper domain to permeabilized ileal strips evoked a Ca2+-independent contraction and resulted in myosin regulatory light chain diphosphorylation at Ser19and Thr18. Neither Ca2+-independent force development nor myosin regulatory light chain phosphorylation was elicited by the addition of kinase-dead ZIPK to the ileal strips. The sensitivity of ZIPK-induced contraction to various kinase inhibitors was similar to the in vitro sensitivity of purified ZIPK to these inhibitors. Staurosporine was the most effective ZIPK inhibitor, with a Kivalue calculated to be 2.6 ± 0.3 µmol/L. Through the use of specific kinase inhibitors, we determined that Rho-associated protein kinase and Ca2+/phospholipid-dependent protein kinase (protein kinase C) do not mitigate ZIPK-induced contraction in ileum. Our findings support a role for ZIPK in Ca2+-independent contractile force generation in gastrointestinal smooth muscle.

Publisher

Canadian Science Publishing

Subject

Cell Biology,Molecular Biology,Biochemistry

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