Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 289, Issue 4, Pages L574-L582Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00134.2005
Keywords
myosin light chain phosphatase; RhoA; Rho-activated kinase; voltage-dependent Ca2+ channels
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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 KC1-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.
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