Non-proteolytic functions of calpain-3 in sarcoplasmic reticulum in skeletal muscles

Koichi Ojima, Yasuko Ono, Coen Ottenheijm, Shoji Hata, Hidenori Suzuki, Henk Granzier, Hiroyuki Sorimachi

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Mutations in CAPN3/Capn3, which codes for skeletal muscle-specific calpain-3/p94 protease, are responsible for limb-girdle muscular dystrophy type 2A. Using "knock-in" (referred to as Capn3CS/CS) mice, in which the endogenous calpain-3 is replaced with a mutant calpain-3:C129S, which is a proteolytically inactive but structurally intact calpain-3, we demonstrated in our previous studies that loss of calpain-3 protease activity causes muscular dystrophy [Ojima, K. et al. (2010) J. Clin. Invest. 120, 2672-2683]. However, compared to Capn3-null (Capn3-/-) mice, Capn3 CS/CS mice showed less severe dystrophic symptoms. This suggests that calpain-3 also has a non-proteolytic function. This study aimed to elucidate the non-proteolytic functions of calpain-3 through comparison of Capn3 CS/CS mice with Capn3-/- mice. We found that calpain-3 is a component of the sarcoplasmic reticulum (SR), and that calpain-3 interacts with, but does not proteolyze, typical SR components such as ryanodine receptor and calsequestrin. Furthermore, Capn3CS/CS mice showed that the nonenzymatic role of calpain-3 is required for proper Ca2+ efflux from the SR to cytosol during muscle contraction. These results indicate that calpain-3 functions as a nonenzymatic element for the Ca2+ efflux machinery in the SR, rather than as a protease. Thus, defects in the nonenzymatic function of calpain-3 must also be involved in the pathogenesis of limb-girdle muscular dystrophy type 2A.

Original languageEnglish (US)
Pages (from-to)439-449
Number of pages11
JournalJournal of Molecular Biology
Volume407
Issue number3
DOIs
StatePublished - Apr 1 2011

Keywords

  • calpainopathy
  • limb-girdle muscular dystrophy type 2A
  • protease
  • proteolysis
  • ryanodine receptor

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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