Role of the JP45-calsequestrin complex on calcium entry in slow twitch skeletal muscles

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Abstract

© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. We exploited a variety of mouse models to assess the roles of JP45-CASQ1 (CASQ, calsequestrin) and JP45-CASQ2 on calcium entry in slow twitch muscles. In flexor digitorum brevis (FDB) fibers isolated from JP45-CASQ1-CASQ2 tripleKOmice, calcium transients induced by tetanic stimulation rely on calcium entry via La 3+ - and nifedipine-sensitive calcium channels. The comparison of excitation-coupled calcium entry (ECCE) between FDB fibers from WT, JP45KO, CASQ1KO, CASQ2KO, JP45-CASQ1 double KO, JP45-CASQ2 double KO, and JP45- CASQ1-CASQ2 triple KO shows that ECCE enhancement requires ablation of both CASQs and JP45. Calcium entry activated by ablation of both JP45-CASQ1 and JP45-CASQ2 complexes supports tetanic force development in slow twitch soleus muscles. In addition, we show that CASQs interact with JP45 at Ca 2+ concentrations similar to those present in the lumen of the sarcoplasmic reticulum at rest, whereas Ca 2+ concentrations similar to those present in the SR lumen after depolarizationinduced calcium release cause the dissociation of JP45 from CASQs. Our results show that the complex JP45-CASQs is a negative regulator of ECCE and that tetanic force development in slow twitch muscles is supported by the dynamic interaction between JP45 and CASQs.

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Mosca, B., Eckhardt, J., Bergamelli, L., Treves, S., Bongianino, R., De Negri, M., … Zorzato, F. (2016). Role of the JP45-calsequestrin complex on calcium entry in slow twitch skeletal muscles. Journal of Biological Chemistry, 291(28), 14555–14565. https://doi.org/10.1074/jbc.M115.709071

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