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This Article Full Text Full Text (PDF) All Versions of this Article: 289/4/L574    most recent 00134.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Liu, C. Articles by Janssen, L. J. Search for Related Content PubMed PubMed Citation Articles by Liu, C. Articles by Janssen, L. J.

Regulation of Rho/ROCK signaling in airway smooth muscle by membrane potential and [Ca²⁺]_i

Asthma Research Group, Firestone Institute for Respiratory Health, St. Joseph's Hospital; and the Department of Medicine, McMaster University, Hamilton, Ontario, Canada

Submitted 23 March 2005 ; accepted in final form 20 May 2005

Recently, we have shown that Rho and Rho-activated kinase (ROCK) may become activated by high-millimolar KCl, which had previously been widely assumed to act solely through opening of voltage-dependent Ca²⁺ channels. In this study, we explored in more detail the relationship between membrane depolarization, Ca²⁺ currents, and activation of Rho/ROCK in bovine tracheal smooth muscle. Ca²⁺ currents began to activate at membrane voltages more positive than –40 mV and were maximally activated above 0 mV; at the same time, these underwent time- and voltage-dependent inactivation. Depolarizing intact tissues by KCl challenge evoked contractions that were blocked equally, and in a nonadditive fashion, by nifedipine or by the ROCK inhibitor Y-27632. Other agents that elevate intracellular calcium concentration ([Ca²⁺]_i) by pathways independent of G protein-coupled receptors, namely the SERCA-pump inhibitor cyclopiazonic acid and the Ca²⁺ ionophore A-23187, evoked contractions that were also largely reduced by Y-27632. KCl directly increased Rho and ROCK activities in a concentration-dependent fashion that paralleled closely the effect of KCl on tone and [Ca²⁺]_i, as well as the voltage-dependent Ca²⁺ currents that were measured over the voltage ranges that are evoked by 0–120 mM KCl. Through the use of various pharmacological inhibitors, we ruled out roles for Ca²⁺/calmodulin-dependent CaM kinase II, protein kinase C, and protein kinase A in mediating the KCl-stimulated changes in tone and Rho/ROCK activities. In conclusion, Rho is activated by elevation of [Ca²⁺]_i (although the signal transduction pathway underlying this Ca²⁺ dependence is still unclear) and possibly also by membrane depolarization per se.

myosin light chain phosphatase; RhoA; Rho-activated kinase; voltage-dependent Ca²⁺ channels

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