Non-Proteolytic Functions of Calpain-3 in Sarcoplasmic Reticulum in Skeletal Muscles
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 Capn3 CS/CS ) mice, in which the endogenous calpain-3 is replaced with a mutant calpain-3:C129S, which is a proteoly...
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| Veröffentlicht in: | Journal of molecular biology 2011-04, Vol.407 (3), p.439-449 |
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| creator | Ojima, Koichi Ono, Yasuko Ottenheijm, Coen Hata, Shoji Suzuki, Hidenori Granzier, Henk Sorimachi, Hiroyuki |
| description | 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
Capn3
CS/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,
Capn3
CS/CS
mice showed that the nonenzymatic role of calpain-3 is required for proper Ca
2+ efflux from the SR to cytosol during muscle contraction. These results indicate that calpain-3 functions as a nonenzymatic element for the Ca
2+ 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. |
| doi_str_mv | 10.1016/j.jmb.2011.01.057 |
| format | Article |
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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
Capn3
CS/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,
Capn3
CS/CS
mice showed that the nonenzymatic role of calpain-3 is required for proper Ca
2+ efflux from the SR to cytosol during muscle contraction. These results indicate that calpain-3 functions as a nonenzymatic element for the Ca
2+ 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.</description><identifier>ISSN: 0022-2836</identifier><identifier>EISSN: 1089-8638</identifier><identifier>DOI: 10.1016/j.jmb.2011.01.057</identifier><identifier>PMID: 21295580</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; calcium ; calpain ; Calpain - genetics ; Calpain - metabolism ; calpainopathy ; Cercopithecus aethiops ; COS Cells ; cytosol ; enzyme activity ; Humans ; limb-girdle muscular dystrophy type 2A ; Mice ; Mice, Inbred C57BL ; Mice, Inbred Strains ; muscle contraction ; Muscle Proteins - genetics ; Muscle Proteins - metabolism ; Muscle, Skeletal - metabolism ; muscular dystrophy ; mutants ; mutation ; pathogenesis ; protease ; proteolysis ; ryanodine receptor ; sarcoplasmic reticulum ; Sarcoplasmic Reticulum - metabolism</subject><ispartof>Journal of molecular biology, 2011-04, Vol.407 (3), p.439-449</ispartof><rights>2011 Elsevier Ltd</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><rights>2011 Elsevier Ltd. All rights reserved. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c572t-c36930ac6e32d4ed407a82e9739026e02028e58be8dd2c550e8ff190cfda3e083</citedby><cites>FETCH-LOGICAL-c572t-c36930ac6e32d4ed407a82e9739026e02028e58be8dd2c550e8ff190cfda3e083</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jmb.2011.01.057$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21295580$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ojima, Koichi</creatorcontrib><creatorcontrib>Ono, Yasuko</creatorcontrib><creatorcontrib>Ottenheijm, Coen</creatorcontrib><creatorcontrib>Hata, Shoji</creatorcontrib><creatorcontrib>Suzuki, Hidenori</creatorcontrib><creatorcontrib>Granzier, Henk</creatorcontrib><creatorcontrib>Sorimachi, Hiroyuki</creatorcontrib><title>Non-Proteolytic Functions of Calpain-3 in Sarcoplasmic Reticulum in Skeletal Muscles</title><title>Journal of molecular biology</title><addtitle>J Mol Biol</addtitle><description>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
Capn3
CS/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,
Capn3
CS/CS
mice showed that the nonenzymatic role of calpain-3 is required for proper Ca
2+ efflux from the SR to cytosol during muscle contraction. These results indicate that calpain-3 functions as a nonenzymatic element for the Ca
2+ 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.</description><subject>Animals</subject><subject>calcium</subject><subject>calpain</subject><subject>Calpain - genetics</subject><subject>Calpain - metabolism</subject><subject>calpainopathy</subject><subject>Cercopithecus aethiops</subject><subject>COS Cells</subject><subject>cytosol</subject><subject>enzyme activity</subject><subject>Humans</subject><subject>limb-girdle muscular dystrophy type 2A</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred Strains</subject><subject>muscle contraction</subject><subject>Muscle Proteins - genetics</subject><subject>Muscle Proteins - metabolism</subject><subject>Muscle, Skeletal - metabolism</subject><subject>muscular dystrophy</subject><subject>mutants</subject><subject>mutation</subject><subject>pathogenesis</subject><subject>protease</subject><subject>proteolysis</subject><subject>ryanodine receptor</subject><subject>sarcoplasmic reticulum</subject><subject>Sarcoplasmic Reticulum - metabolism</subject><issn>0022-2836</issn><issn>1089-8638</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkVFrFDEQx4NY7Fn9AL7ovvVpz0myyWYRBDlaK7Qqtn0OuexszZlNzmS30G9vrleLvigM5GF--TEzf0JeUVhSoPLtZrkZ10sGlC6hlGifkAUF1dVKcvWULAAYq5ni8pA8z3kDAII36hk5ZJR1QihYkKvPMdRfU5ww-rvJ2ep0DnZyMeQqDtXK-K1xoeaVC9WlSTZuvcljwb5hgWc_j_edH-hxMr66mLP1mF-Qg8H4jC8f3iNyfXpytTqrz798_LT6cF5b0bKptlx2HIyVyFnfYN9AaxTDruUdMInAgCkUao2q75kVAlANA-3ADr3hCIofkfd773Zej9hbDFMyXm-TG02609E4_XcnuO_6Jt5qDkLSpiuC4wdBij9nzJMeXbbovQkY56w7aBqpqGz_S6oiLHMzWUi6J22KOSccHuehoHex6Y0useldbBpKiZ399Z-LPP74nVMB3uyBwURtbpLL-vqyGETJtJECdqu82xNYDn7rMOlsHQaLvUtoJ91H948BfgFxDLIo</recordid><startdate>20110401</startdate><enddate>20110401</enddate><creator>Ojima, Koichi</creator><creator>Ono, Yasuko</creator><creator>Ottenheijm, Coen</creator><creator>Hata, Shoji</creator><creator>Suzuki, Hidenori</creator><creator>Granzier, Henk</creator><creator>Sorimachi, Hiroyuki</creator><general>Elsevier Ltd</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7QP</scope><scope>5PM</scope></search><sort><creationdate>20110401</creationdate><title>Non-Proteolytic Functions of Calpain-3 in Sarcoplasmic Reticulum in Skeletal Muscles</title><author>Ojima, Koichi ; Ono, Yasuko ; Ottenheijm, Coen ; Hata, Shoji ; Suzuki, Hidenori ; Granzier, Henk ; Sorimachi, Hiroyuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c572t-c36930ac6e32d4ed407a82e9739026e02028e58be8dd2c550e8ff190cfda3e083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>calcium</topic><topic>calpain</topic><topic>Calpain - genetics</topic><topic>Calpain - metabolism</topic><topic>calpainopathy</topic><topic>Cercopithecus aethiops</topic><topic>COS Cells</topic><topic>cytosol</topic><topic>enzyme activity</topic><topic>Humans</topic><topic>limb-girdle muscular dystrophy type 2A</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Inbred Strains</topic><topic>muscle contraction</topic><topic>Muscle Proteins - genetics</topic><topic>Muscle Proteins - metabolism</topic><topic>Muscle, Skeletal - metabolism</topic><topic>muscular dystrophy</topic><topic>mutants</topic><topic>mutation</topic><topic>pathogenesis</topic><topic>protease</topic><topic>proteolysis</topic><topic>ryanodine receptor</topic><topic>sarcoplasmic reticulum</topic><topic>Sarcoplasmic Reticulum - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ojima, Koichi</creatorcontrib><creatorcontrib>Ono, Yasuko</creatorcontrib><creatorcontrib>Ottenheijm, Coen</creatorcontrib><creatorcontrib>Hata, Shoji</creatorcontrib><creatorcontrib>Suzuki, Hidenori</creatorcontrib><creatorcontrib>Granzier, Henk</creatorcontrib><creatorcontrib>Sorimachi, Hiroyuki</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ojima, Koichi</au><au>Ono, Yasuko</au><au>Ottenheijm, Coen</au><au>Hata, Shoji</au><au>Suzuki, Hidenori</au><au>Granzier, Henk</au><au>Sorimachi, Hiroyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Non-Proteolytic Functions of Calpain-3 in Sarcoplasmic Reticulum in Skeletal Muscles</atitle><jtitle>Journal of molecular biology</jtitle><addtitle>J Mol Biol</addtitle><date>2011-04-01</date><risdate>2011</risdate><volume>407</volume><issue>3</issue><spage>439</spage><epage>449</epage><pages>439-449</pages><issn>0022-2836</issn><eissn>1089-8638</eissn><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
Capn3
CS/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,
Capn3
CS/CS
mice showed that the nonenzymatic role of calpain-3 is required for proper Ca
2+ efflux from the SR to cytosol during muscle contraction. These results indicate that calpain-3 functions as a nonenzymatic element for the Ca
2+ 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.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>21295580</pmid><doi>10.1016/j.jmb.2011.01.057</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of molecular biology, 2011-04, Vol.407 (3), p.439-449 |
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| language | eng |
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| source | MEDLINE; ScienceDirect Freedom Collection (Elsevier) |
| subjects | Animals calcium calpain Calpain - genetics Calpain - metabolism calpainopathy Cercopithecus aethiops COS Cells cytosol enzyme activity Humans limb-girdle muscular dystrophy type 2A Mice Mice, Inbred C57BL Mice, Inbred Strains muscle contraction Muscle Proteins - genetics Muscle Proteins - metabolism Muscle, Skeletal - metabolism muscular dystrophy mutants mutation pathogenesis protease proteolysis ryanodine receptor sarcoplasmic reticulum Sarcoplasmic Reticulum - metabolism |
| title | Non-Proteolytic Functions of Calpain-3 in Sarcoplasmic Reticulum in Skeletal Muscles |
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