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Opportunities to Target Specific Contractile Abnormalities with Smooth Muscle Protein Kinase Inhibitors
Smooth Muscle Research Group and Department of Biochemistry & Molecular Biology, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta, T2N 4Z6, Canada
* Author to whom correspondence should be addressed.
Received: 8 April 2010; in revised form: 26 April 2010 / Accepted: 24 May 2010 / Published: 26 May 2010
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
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Ulke-Lemée, A.; MacDonald, J.A. Opportunities to Target Specific Contractile Abnormalities with Smooth Muscle Protein Kinase Inhibitors. Pharmaceuticals 2010, 3, 1739-1760.
Ulke-Lemée A, MacDonald JA. Opportunities to Target Specific Contractile Abnormalities with Smooth Muscle Protein Kinase Inhibitors. Pharmaceuticals. 2010; 3(6):1739-1760.
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.