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Protein Kinase C- Regulates Local Calcium Signaling in Airway Smooth Muscle Cells

¹ Center for Cardiovascular Sciences, Albany Medical College, Albany, New York; ² Department of Physiology and Biophysics, Robert Wood Johnson Medical School, Piscataway, New Jersey; and ³ Department of Biological Chemistry, Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto, Japan

Correspondence and requests for reprints should be addressed to Yong-Xiao Wang, M.D., Ph.D., Albany Medical College, Center for Cardiovascular Sciences (MC-8), 47 New Scotland Ave., Albany, NY 12208. E-mail: wangy{at}mail.amc.edu

Protein kinase C (PKC) is known to regulate ryanodine receptor (RyR)–mediated local Ca²⁺ signaling (Ca²⁺ spark) in airway and vascular smooth muscle cells (SMCs), but its specific molecular mechanisms and functions still remain elusive. In this study, we reveal that, in airway SMCs, specific PKC peptide inhibitor and gene deletion significantly increased the frequency of Ca²⁺ sparks, and decreased the amplitude of Ca²⁺ sparks in the presence of xestospogin-C to eliminate functional inositol 1,4,5-triphosphate receptors. PKC activation with phorbol-12-myristate-13-acetate significantly decreased Ca²⁺ spark frequency and increased Ca²⁺ spark amplitude. The effect of PKC inhibition or activation on Ca²⁺ sparks was completely lost in PKC^–/– cells. PKC inhibition or PKC activation was unable to affect Ca²⁺ sparks in RyR1^–/– and RyR1^+/– cells. Modification of RyR2 activity by FK506-binding protein 12.6 homozygous or RyR2 heterozygous gene deletion did not prevent the effect of PKC inhibition or activation. RyR3 homogenous gene deletion did not block the effect of PKC inhibition and activation, either. PKC inhibition promotes agonist-induced airway muscle contraction, whereas PKC activation produces an opposite effect. Taken together, these results indicate that PKC regulates Ca²⁺ sparks by specifically interacting with RyR1, which plays an important role in the control of contractile responses in airway SMCs.

Key Words: protein kinase C • local calcium signaling • ryanodine receptor • contraction • airway myocytes

CLINICAL RELEVANCE This study reveals that protein kinase C (PKC)- regulates local Ca2+ signaling by specifically interacting with ryanodine receptor (RyR) 1, thereby modulating contractile responses in airway smooth muscle cells. Thus, PKC- and RyR1 may become new therapeutic targets for asthma and other lung diseases.

 

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