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(Circulation Research. 2003;93:481.)
© 2003 American Heart Association, Inc.

Editorial

Rho Signaling

Agonist Stimulation and Depolarization Come Together

Frank V. Brozovich

From the Departments of Physiology and Biophysics, and Medicine (Cardiology), Case Western Reserve University, Cleveland, Ohio.

Correspondence to Frank V. Brozovich, Department of Physiology and Biophysics, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106-4970. E-mail fxb9@cwru.edu

Key Words: force enhancement • smooth muscle • Rho-kinase • signaling

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Force development in smooth muscle is dependent on Ca²⁺/calmodulin (Ca²⁺/CaM) activation of myosin light chain kinase (MLCK) and the subsequent phosphorylation of the regulatory myosin light chain (MLC₂₀).¹ However, when smooth muscle is stimulated with agonists² or by direct activation of the G-proteins,^3–6 a higher force is developed for a given [Ca²⁺] than for depolarization. Although the mechanism for this Ca²⁺ sensitization of the contractile filaments is still the subject of investigation, evidence suggests that the signaling pathway may involve either the activation of Rho (for reviews see^7–9) and/or protein kinase C (PKC),^10,11 although a pathway involving Rho and subsequent activation of Rho-kinase is more widely accepted. Agonist stimulation of smooth muscle can be divided into two phases: an initial rapid, transient increase in Ca²⁺ and MLC₂₀ phosphorylation, and a subsequent phase of a sustained force despite lower levels of Ca²⁺ and MLC₂₀ phosphorylation.¹² There is evidence that the sustained phase of force maintenance is dependent on the activation of Rho.¹³

Although uncertainty exists regarding the mechanism by which receptor-mediated activation of the G-proteins leads to force enhancement, it is generally accepted that membrane depolarization leads to an increase in intracellular [Ca²⁺] and a Ca²⁺-dependent activation of MLCK to increase MLC₂₀ phosphorylation and force. Thus, it has become dogma that depolarization leads to only an increase in Ca²⁺ and a subsequent activation of MLCK, without the activation of additional signaling pathways. Challenging these generally accepted principles is recent evidence that Rho-kinase inhibition almost . . . [Full Text of this Article]

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