DIFFERENTIAL DEVELOPMENT OF CARBACHOL-INDUCED DESENSITIZATION IN RECEPTOR-MEDIATED Ca²⁺ INFLUX AND Ca²⁺ RELEASE PATHWAYS IN SMOOTH MUSCLE OF GUINEA-PIG TAENIA CAECI

Authors: Hishinuma, Shigeru; Matsumoto, Yukio; Sato, Ryo; Saito, Masaki

Source: Clinical and Experimental Pharmacology and Physiology, Volume 34, Number 3, March 2007 , pp. 191-197(7)

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Abstract:

SUMMARY

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We have found that development of carbachol (CCh)-induced desensitization to receptor agonists, but not to receptor by-passed stimulation, is transiently interrupted by a Ca²⁺-dependent resensitization during the early stage in the smooth muscle of guinea-pig taenia caeci. To further characterize the receptor-mediated signal transduction pathways involved in this peculiar desensitization process, we examined the desensitization processes during Ca²⁺ influx- and Ca²⁺ release-mediated contractions in response to activation of muscarinic receptors or histamine H₁ receptors.

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Desensitization treatment with 10⁻⁴ mol/L CCh for 30 min in the presence of extracellular Ca²⁺ resulted in desensitization to the muscarinic agonists McN-A-343 or AHR-602, which are known to induce contraction only in the presence of extracellular Ca²⁺ in taenia caeci. The development of desensitization to these agonists was interrupted by a transient resensitization at 1 min. In contrast, the transient resensitization phase was lost following removal of extracellular Ca²⁺ during the desensitization treatment with CCh; under these conditions, the desensitization developed gradually without an apparent resensitization phase.

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Contractions to 10⁻⁴ mol/L CCh and 10⁻⁴ mol/L histamine in the absence of extracellular Ca²⁺ were gradually desensitized without a resensitization phase following the CCh desensitization treatment, irrespective of the presence or absence of extracellular Ca²⁺ during CCh treatment, although the onset of the desensitization was delayed under Ca²⁺-free conditions.

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These results suggest that the receptor-mediated Ca²⁺ influx and Ca²⁺ release pathways are differentially desensitized to CCh and that the transient resensitization appears to regulate the desensitization process in response to Ca²⁺ influx-mediated contraction. Such differential processes of desensitization in receptor-mediated bifurcated signalling pathways may determine cellular responsiveness to certain types of stimuli, depending on the different Ca²⁺ sources required for contraction.

Keywords: AHR-602; Ca2+ influx; Ca2+ release; carbachol; desensitization; histamine H1 receptor; McN-A-343; muscarinic M3 receptor; resensitization; smooth muscle

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1440-1681.2007.04571.x

Publication date: 2007-03-01