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A Signal Transduction Pathway Model Prototype II: Application to Ca²⁺-Calmodulin Signaling and Myosin Light Chain Phosphorylation

Department of Molecular Pharmacology and Drug Discovery Program, Northwestern University, Chicago, Illinois

Correspondence: Address reprint requests to Prof. Thomas J. Lukas, Dept. of Molecular Pharmacology and Biological Chemistry, Northwestern University, Ward 8-200, 303 E. Chicago Ave., Mail Code S-215, Chicago, IL 60611. Tel.: 312-503-0847; E-mail: t-lukas{at}northwestern.edu.

An agonist-initiated Ca²⁺ signaling model for calmodulin (CaM) coupled to the phosphorylation of myosin light chains was created using a computer-assisted simulation environment. Calmodulin buffering was introduced as a module for directing sequestered CaM to myosin light chain kinase (MLCK) through Ca²⁺-dependent release from a buffering protein. Using differing simulation conditions, it was discovered that CaM buffering allowed transient production of more Ca²⁺-CaM-MLCK complex, resulting in elevated myosin light chain phosphorylation compared to nonbuffered control. Second messenger signaling also impacts myosin light chain phosphorylation through the regulation of myosin light chain phosphatase (MLCP). A model for MLCP regulation via its regulatory MYPT1 subunit and interaction of the CPI-17 inhibitor protein was assembled that incorporated several protein kinase subsystems including Rho-kinase, protein kinase C (PKC), and constitutive MYPT1 phosphorylation activities. The effects of the different routes of MLCP regulation depend upon the relative concentrations of MLCP compared to CPI-17, and the specific activities of protein kinases such as Rho and PKC. Phosphorylated CPI-17 (CPI-17P) was found to dynamically control activity during agonist stimulation, with the assumption that inhibition by CPI-17P (resulting from PKC activation) is faster than agonist-induced phosphorylation of MYPT1. Simulation results are in accord with literature measurements of MLCP and CPI-17 phosphorylation states during agonist stimulation, validating the predictive capabilities of the system.

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