Various pharmacological agents designed to modulate plasma membrane ion channels appear to significantly affect intracellular Ca(2+) signaling when acting on their target receptor. Some agents could also cross-react (modulate channels or receptors beyond their putative target) with intracellular Ca(2+) transporters. This paper investigated the potential of thirty putative modulators of either plasma membrane K(+), Na(+) or transient receptor potential (TRP) channels to cross-react with intracellular Ca(2+) release channels [i.e., ryanodine receptors (RyRs)] from skeletal muscle sarcoplasmic reticulum (SR). Screening for cross-reactivity of these various agents was performed by measuring the rate of spontaneous Ca(2+) leak or caffeine-induced Ca(2+) release from SR microsomes. Four of the agents displayed a strong cross-reactivity and were further evaluated with skeletal RyR (RyR1) reconstituted into planar bilayers. UCL 1684 (K(+) channel antagonist) and lamotrigine (Na(+) channel antagonist) were found to significantly inhibit the RyR1-mediated caffeine-induced Ca(2+) release. TRP channel agonists anandamide and (-)menthol were found to inhibit and activate RyR1, respectively. High concentrations of nine other agents produced partial inhibition of RyR1-mediated Ca(2+) release from SR microsomes. Various pharmacological agents, especially TRP modulators, also inhibited a minor RyR1-independent component of the SR Ca(2+) leak. Overall, ~43% of the agents selected cross-reacted with RyR1-mediated and/or RyR1-independent Ca(2+) leak from intracellular stores.Thus, cross-reactivity should be considered when using pharmacological agents to determine the role of plasmalemma channels in Ca(2+) homeostasis.
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