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

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-27...