title: Mitsugumin 53 regulates extracellular Ca2+entry and intracellular Ca2+release via Orai1 and RyR1 in skeletal muscle.
abstract: Mitsugumin 53 (MG53) participates in the membrane repair of various cells, and skeletal muscle is the major tissue that expresses MG53. Except for the regulatory effects of MG53 on SERCA1a, the role(s) of MG53 in the unique functions of skeletal muscle such as muscle contraction have not been well examined. Here, a new MG53-interacting protein, Orai1, is identified in skeletal muscle. To examine the functional relevance of the MG53-Orai1 interaction, MG53 was over-expressed in mouse primary or C2C12 skeletal myotubes and the functional properties of the myotubes were examined using cell physiological and biochemical approaches. The PRY-SPRY region of MG53 binds to Orai1, and MG53 and Orai1 are co-localized in the plasma membrane of skeletal myotubes. MG53-Orai1 interaction enhances extracellular Ca2+entry via a store-operated Ca2+entry (SOCE) mechanism in skeletal myotubes. Interestingly, skeletal myotubes over-expressing MG53 or PRY-SPRY display a reduced intracellular Ca2+release in response to K+-membrane depolarization or caffeine stimulation, suggesting a reduction in RyR1 channel activity. Expressions of TRPC3, TRPC4, and calmodulin 1 are increased in the myotubes, and MG53 directly binds to TRPC3, which suggests a possibility that TRPC3 also participates in the enhanced extracellular Ca2+entry. Thus, MG53 could participate in regulating extracellular Ca2+entry via Orai1 during SOCE and also intracellular Ca2+release via RyR1 during skeletal muscle contraction.
authors.affiliation: Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea.
authors.forename: Mi Kyoung
authors.initials: MK
authors.lastname: Ahn
authors.affiliation: Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea.
authors.forename: Keon Jin
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Center for Cardiovascular Sciences, Department of Molecular and Cellular Physiology, Albany Medical College, 43 New Scotland Avenue, Albany, New York 12208, USA.
authors.forename: Chuanxi
authors.initials: C
authors.lastname: Cai
authors.affiliation: Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea.
authors.forename: Mei
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, College of Medicine, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Republic of Korea.
authors.forename: Chung-Hyun
authors.initials: CH
authors.lastname: Cho
authors.affiliation: Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, 360 W. 12th Ave, Columbus, Ohio 43210, USA.
authors.forename: Jianjie
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Physiology, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea.
authors.forename: Eun Hui
authors.initials: EH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism; D000071740:ORAI1 Protein / Q000378:metabolism*; D011485:Protein Binding; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism
chemical_list: C000607143:CALM1 protein, human; D002147:Calmodulin; D002352:Carrier Proteins; C538824:MG53 protein, mouse; D008565:Membrane Proteins; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; D019837:Ryanodine Receptor Calcium Release Channel; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C489571:TRPC4 ion channel; C000592747:ryanodine receptor 1, mouse; D002118:Calcium