A new cytoplasmic interaction between junctin and ryanodine receptor Ca2+ release channels

Linwei Li, Shamaruh Mirza, Spencer J Richardson, Esther M. Gallant, Chris Thekkedam, Suzy M Pace, Francesco Zorzato, Dan Liu, Nicole A Beard, Angela F. Dulhunty

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Junctin, a non-catalytic splice variant encoded by the aspartate-β-hydroxylase (Asph) gene, is inserted into the membrane of the sarcoplasmic reticulum (SR) Ca(2+) store where it modifies Ca(2+) signalling in the heart and skeletal muscle through its regulation of ryanodine receptor (RyR) Ca(2+) release channels. Junctin is required for normal muscle function as its knockout leads to abnormal Ca(2+) signalling, muscle dysfunction and cardiac arrhythmia. However, the nature of the molecular interaction between junctin and RyRs is largely unknown and was assumed to occur only in the SR lumen. We find that there is substantial binding of RyRs to full junctin, and the junctin luminal and, unexpectedly, cytoplasmic domains. Binding of these different junctin domains had distinct effects on RyR1 and RyR2 activity: full junctin in the luminal solution increased RyR channel activity by ∼threefold, the C-terminal luminal interaction inhibited RyR channel activity by ∼50%, and the N-terminal cytoplasmic binding produced an ∼fivefold increase in RyR activity. The cytoplasmic interaction between junctin and RyR is required for luminal binding to replicate the influence of full junctin on RyR1 and RyR2 activity. The C-terminal domain of junctin binds to residues including the S1-S2 linker of RyR1 and N-terminal domain of junctin binds between RyR1 residues 1078 and 2156.

Original languageEnglish
Pages (from-to)951-963
Number of pages13
JournalJournal of Cell Science
Volume128
Issue number5
DOIs
Publication statusPublished - 1 Mar 2015
Externally publishedYes

    Fingerprint

Cite this

Li, L., Mirza, S., Richardson, S. J., Gallant, E. M., Thekkedam, C., Pace, S. M., ... Dulhunty, A. F. (2015). A new cytoplasmic interaction between junctin and ryanodine receptor Ca2+ release channels. Journal of Cell Science, 128(5), 951-963. https://doi.org/10.1242/jcs.160689