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Agonist-induced phasic and tonic responses in smooth muscle are mediated by InsP₃

Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK

^* Author for correspondence (e-mail: j.mccarron{at}bio.gla.ac.uk )

Accepted 11 March 2002

Many cellular functions are regulated by agonist-induced InsP₃-evoked Ca²⁺ release from the internal store. In non-excitable cells, predominantly, the initial Ca²⁺ release from the store by InsP₃ is followed by a more sustained elevation in [Ca²⁺]_i via store-operated Ca²⁺ channels as a consequence of depletion of the store. Here, in smooth muscle, we report that the initial transient increase in Ca²⁺, from the internal store, is followed by a sustained response also as a consequence of depletion of the store (by InsP₃), but, influx occurs via voltage-dependent Ca²⁺ channels. Contractions were measured in pieces of whole distal colon and membrane currents and [Ca²⁺]_i in single colonic myocytes. Carbachol evoked phasic and tonic contractions; only the latter were abolished in Ca²⁺-free solution. The tonic component was blocked by the voltage-dependent Ca²⁺ channel blocker nimodipine but not by the store-operated channel blocker SKF 96365. InsP₃ receptor inhibition, with 2-APB, attenuated both the phasic and tonic components. InsP₃ may regulate tonic contractions via sarcolemma Ca²⁺ entry. In single cells, depolarisation (to -20 mV) elevated [Ca²⁺]_i and activated spontaneous transient outward currents (STOCs). CCh suppressed STOCs, as did caffeine and InsP₃. InsP₃ receptor blockade by 2-APB or heparin prevented CCh suppression of STOCs; protein kinase inhibition by H-7 or PKC_19-36 did not. InsP₃ suppressed STOCs by depleting a Ca²⁺ store accessed separately by the ryanodine receptor (RyR). Thus depletion of the store by RyR activators abolished the InsP₃-evoked Ca²⁺ transient. RyR inhibition (by tetracaine) reduced only STOCs but not the InsP₃ transient. InsP₃ contributes to both phasic and tonic contractions. In the former, muscarinic receptor-evoked InsP₃ releases Ca²⁺ from an internal store accessed by both InsP₃ and RyR. Depletion of this store by InsP₃ alone suppresses STOCs, depolarises the sarcolemma and permits entry of Ca²⁺ to generate the tonic component. Therefore, by lowering the internal store Ca²⁺ content, InsP₃ may generate a sustained smooth muscle contraction. These results provide a mechanism to account for phasic and tonic smooth muscle contraction following receptor activation.

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