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Two distinct signaling pathways for regulation of spontaneous local Ca2+ release by phospholipase C in airway smooth muscle cells

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Abstract

Spontaneous local Ca2+ release events have been observed in airway smooth muscle cells (SMCs), but the underlying mechanisms are largely unknown. Considering that each type of SMCs may use its own mechanisms to regulate local Ca2+ release events, we sought to investigate the signaling pathway for spontaneous local Ca2+ release events in freshly isolated mouse airway SMCs using a laser scanning confocal microscope. Application of ryanodine to block ryanodine receptors (RyRs) abolished spontaneous local Ca2+ release events, indicating that these events are RyR-mediated Ca2+ sparks. Inhibition of inositol 1,4,5-triphosphate receptors (IP3Rs) by 2-aminoethoxydiphenyl-borate (2-APB) or xestospongin-C significantly blocked the activity of Ca2+ sparks. Under patch clamp conditions, dialysis of IP3 to activate IP3Rs increased the activity of local Ca2+ events in control cells but had no effect in ryanodine-pretreated cells. The RyR agonist caffeine augmented the frequency of Ca2+ sparks in cells pretreated with and without 2-APB or xestospongin-C. The specific phospholipase C (PLC) blocker U73122 decreased the activity of Ca2+ sparks and prevented xestospongin-C from producing the inhibitory effect. The protein kinase C (PKC) activator 1-oleoyl-2-acetyl-glycerol or phorbol-12-myristate-13-acetate inhibited Ca2+ sparks, whereas the PKC inhibitor chelerythrine, PKCɛ inhibitory peptide, or PKCɛ gene knockout produced an opposite effect. Collectively, our data suggest that the basal activation of PLC regulates the activity of RyR-mediated, spontaneous Ca2+ sparks in airway SMCs through two distinct signaling pathways: a positive IP3-IP3R pathway and a negative diacylglycerol–PKCɛ pathway.

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Acknowledgement

The authors thank Ms. Jodi Heim for her excellent technical assistance. This work was supported by the American Heart Association (AHA; Y.-M.Z. and Y.-X.W.) and National Institutes of Health (NIH; Y.-X.W.).

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  1. Center for Cardiovascular Sciences, Albany Medical College (MC-8), 47 New Scotland Avenue, Albany, NY, 12208, USA

    Qing-Hua Liu, Yun-Min Zheng & Yong-Xiao Wang

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  1. Qing-Hua Liu
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Correspondence to Yong-Xiao Wang.

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Liu, QH., Zheng, YM. & Wang, YX. Two distinct signaling pathways for regulation of spontaneous local Ca2+ release by phospholipase C in airway smooth muscle cells. Pflugers Arch - Eur J Physiol 453, 531–541 (2007). https://doi.org/10.1007/s00424-006-0130-1

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