Pharmaceuticals 2010, 3(6), 1739-1760; doi:10.3390/ph3061739
Review

Opportunities to Target Specific Contractile Abnormalities with Smooth Muscle Protein Kinase Inhibitors

email and * email
Received: 8 April 2010; in revised form: 26 April 2010 / Accepted: 24 May 2010 / Published: 26 May 2010
(This article belongs to the Special Issue Protein Kinase Inhibitors)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract: Smooth muscle is a major component of most hollow organ systems (e.g., airways, vasculature, bladder and gut/gastrointestine); therefore, the coordinated regulation of contraction is a key property of smooth muscle. When smooth muscle functions normally, it contributes to general health and wellness, but its dysfunction is associated with morbidity and mortality. Rho-associated protein kinase (ROCK) is central to calcium-independent, actomyosin-mediated contractile force generation in the vasculature, thereby playing a role in smooth muscle contraction, cell motility and adhesion. Recent evidence supports an important role for ROCK in the increased vasoconstriction and remodeling observed in various models of hypertension. This review will provide a commentary on the development of specific ROCK inhibitors and their clinical application. Fasudil will be discussed as an example of bench-to-bedside development of a clinical therapeutic that is used to treat conditions of vascular hypercontractility. Due to the wide spectrum of biological processes regulated by ROCK, many additional clinical indications might also benefit from ROCK inhibition. Apart from the importance of ROCK in smooth muscle contraction, a variety of other protein kinases are known to play similar roles in regulating contractile force. The zipper-interacting protein kinase (ZIPK) and integrin-linked kinase (ILK) are two well-described regulators of contraction. The relative contribution of each kinase to contraction depends on the muscle bed as well as hormonal and neuronal stimulation. Unfortunately, specific inhibitors for ZIPK and ILK are still in the development phase, but the success of fasudil suggests that inhibitors for these other kinases may also have valuable clinical applications. Notably, the directed inhibition of ZIPK with a pseudosubstrate molecule shows unexpected effects on the contractility of gastrointestinal smooth muscle.
Keywords: calcium sensitization; zipper-interacting protein kinase; integrin-linked kinase; Rho-associated kinase; myosin phosphatase; myosin light chain diphosphorylation; MYPT1; CPI-17
PDF Full-text Download PDF Full-Text [3244 KB, uploaded 26 May 2010 11:09 CEST]

Export to BibTeX |
EndNote


MDPI and ACS Style

Ulke-Lemée, A.; MacDonald, J.A. Opportunities to Target Specific Contractile Abnormalities with Smooth Muscle Protein Kinase Inhibitors. Pharmaceuticals 2010, 3, 1739-1760.

AMA Style

Ulke-Lemée A, MacDonald JA. Opportunities to Target Specific Contractile Abnormalities with Smooth Muscle Protein Kinase Inhibitors. Pharmaceuticals. 2010; 3(6):1739-1760.

Chicago/Turabian Style

Ulke-Lemée, Annegret; MacDonald, Justin A. 2010. "Opportunities to Target Specific Contractile Abnormalities with Smooth Muscle Protein Kinase Inhibitors." Pharmaceuticals 3, no. 6: 1739-1760.

Pharmaceuticals EISSN 1424-8247 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert