This paper was published as Journal of Pharmacology and Experimental Therapeutics, 2009, 330 (2), pp. 502-512. It is available from http://jpet.aspetjournals.org/content/330/2/502. Doi: 10.1124/jpet.109.153619Metadata only entryUnder physiological circumstances, cellular responses often reflect integration of signaling by two or more different receptors activated coincidentally or sequentially. In addition to heterologous desensitization, there are examples in which receptor activation either reveals or potentiates signaling by a different receptor type, although this is perhaps less well explored. Here, we characterize one such interaction between endogenous receptors in human embryonic kidney 293 cells in which Gαq/11-coupled muscarinic M3 receptors facilitate Ca2+ signaling by Gαs-coupled β2-adrenoceptors. Measurement of changes in intracellular [Ca2+] demonstrated that noradrenaline released Ca2+ from thapsigargin-sensitive intracellular stores only during activation of muscarinic receptors. Agonists with low efficacy for muscarinic receptor-mediated Ca2+ responses facilitated cross-talk more effectively than full agonists. The cross-talk required Gαs and was dependent upon intracellular Ca2+ release channels, particularly inositol (1,4,5)-trisphosphate receptors. However, β2-adrenoceptor-mediated Ca2+ release was independent of measurable increases in phospholipase C activity and resistant to inhibitors of protein kinases A and C. Interestingly, single-cell imaging demonstrated that particularly lower concentrations of muscarinic receptor agonists facilitated marked oscillatory Ca2+ signaling to noradrenaline. Thus, activation of muscarinic M3 receptors profoundly influences the magnitude and oscillatory behavior of intracellular Ca2+ signaling by β2-adrenoceptors. Although these receptor subtypes are often coexpressed and mediate contrasting acute physiological effects, altered oscillatory Ca2+ signaling suggests that cross-talk could influence longer term events through, for example, regulating gene transcription
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