Duplex signaling by CaM and Stac3 enhances CaV1.1 function and provides insights into congenital myopathy

Jacqueline Niu, Wanjun Yang, David T. Yue, Takanari Inoue, Manu Ben-Johny

Research output: Contribution to journalArticle

Abstract

CaV1.1 is essential for skeletal muscle excitation-contraction coupling. Its functional expression is tuned by numerous regulatory proteins, yet underlying modulatory mechanisms remain ambiguous as CaV1.1 fails to function in heterologous systems. In this study, by dissecting channel trafficking versus gating, we evaluated the requirements for functional CaV1.1 in heterologous systems. Although coexpression of the auxiliary β subunit is sufficient for surface-membrane localization, this baseline trafficking is weak, and channels elicit a diminished open probability. The regulatory proteins calmodulin and stac3 independently enhance channel trafficking and gating via their interaction with the CaV1.1 carboxy terminus. Myopathic stac3 mutations weaken channel binding and diminish trafficking. Our findings demonstrate that multiple regulatory proteins orchestrate CaV1.1 function via duplex mechanisms. Our work also furnishes insights into the pathophysiology of stac3-associated congenital myopathy and reveals novel avenues for pharmacological intervention.

Original languageEnglish (US)
Pages (from-to)1145-1161
Number of pages17
JournalJournal of General Physiology
Volume150
Issue number8
DOIs
StatePublished - Aug 1 2018

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Myotonia Congenita
Excitation Contraction Coupling
Proteins
Calmodulin
Muscle Contraction
Skeletal Muscle
Pharmacology
Mutation
Membranes

ASJC Scopus subject areas

  • Physiology

Cite this

Duplex signaling by CaM and Stac3 enhances CaV1.1 function and provides insights into congenital myopathy. / Niu, Jacqueline; Yang, Wanjun; Yue, David T.; Inoue, Takanari; Ben-Johny, Manu.

In: Journal of General Physiology, Vol. 150, No. 8, 01.08.2018, p. 1145-1161.

Research output: Contribution to journalArticle

Niu, Jacqueline ; Yang, Wanjun ; Yue, David T. ; Inoue, Takanari ; Ben-Johny, Manu. / Duplex signaling by CaM and Stac3 enhances CaV1.1 function and provides insights into congenital myopathy. In: Journal of General Physiology. 2018 ; Vol. 150, No. 8. pp. 1145-1161.
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