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Hypertrophy in Skeletal Myotubes Induced by Junctophilin-2 Mutant, Y141H, Involves an Increase in Store-operated Ca2+ Entry via Orai1*

  • Jin Seok Woo
    Affiliations
    Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
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  • Chung-Hyun Cho
    Affiliations
    Department of Pharmacology and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
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  • Keon Jin Lee
    Affiliations
    Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
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  • Do Han Kim
    Affiliations
    Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea
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  • Jianjie Ma
    Affiliations
    Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
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  • Eun Hui Lee
    Correspondence
    To whom correspondence should be addressed. Tel.: 82-2-2258-7279; Fax: 82-2-532-9575
    Affiliations
    Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea
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  • Author Footnotes
    * This work was supported by a grant from the Korea Healthcare Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A090047) (to E. H. L.), and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by Ministry of Education, Science and Technology Grants 2010–0022731 (to E. H. L.) and 2010-0028236 (to C. H. C.).
    This article contains supplemental Figs. S1–S5.
Open AccessPublished:March 02, 2012DOI:https://doi.org/10.1074/jbc.M111.304808
      Junctophilins (JPs) play an important role in the formation of junctional membrane complexes (JMC) in striated muscle by physically linking the transverse-tubule and sarcoplasmic reticulum (SR) membranes. Researchers have found five JP2 mutants in humans with hypertrophic cardiomyopathy. Among these, Y141H and S165F are associated with severely altered Ca2+ signaling in cardiomyocytes. We previously reported that S165F also induced both hypertrophy and altered intracellular Ca2+ signaling in mouse skeletal myotubes. In the present study, we attempted to identify the dominant-negative role(s) of Y141H in primary mouse skeletal myotubes. Consistent with S165F, Y141H led to hypertrophy and altered Ca2+ signaling (a decrease in the gain of excitation-contraction coupling and an increase in the resting level of myoplasmic Ca2+). However, unlike S165F, neither ryanodine receptor 1-mediated Ca2+ release from the SR nor the phosphorylation of the mutated JP2 by protein kinase C was related to the altered Ca2+ signaling by Y141H. Instead, abnormal JMC and increased SOCE via Orai1 were found, suggesting that the hypertrophy caused by Y141H progressed differently from S165F. Therefore JP2 can be linked to skeletal muscle hypertrophy via various Ca2+ signaling pathways, and SOCE could be one of the causes of altered Ca2+ signaling observed in muscle hypertrophy.

      Introduction

      In striated muscle, the dihydropyridine receptor (DHPR)
      The abbreviations used are: DHPR
      dihydropyridine receptor
      JP
      junctophilin
      HCM
      hypertrophic cardiomyopathy
      Y141H
      a JP2 mutant at Tyr141
      S165F
      a JP2 mutant at Ser165
      JMC
      junctional membrane complexes
      EC
      excitation-contraction
      SR
      sarcoplasmic reticulum
      RyR
      ryanodine receptor
      SOCE
      store-operated Ca2+ entry
      TRPC
      canonical-type transient receptor potential cation channel
      STIM
      stromal interaction molecule
      qPCR
      quantitative PCR
      CPA
      cyclopiazonic acid
      RFP
      red fluorescent protein
      TEM
      transmission electron microscopy.
      (which is a membrane voltage-sensing protein as well as a Ca2+-entry channel on transverse (t)-tubule membranes) is activated by membrane depolarization, which allows the ryanodine receptor (RyR, which is an internal Ca2+-releasing channel on the sarcoplasmic reticulum (SR) membrane) to release Ca2+ ions from the SR into the myoplasm, and finally induces muscle contraction. This process is called excitation-contraction (EC) coupling (
      • Zucchi R.
      • Ronca-Testoni S.
      The sarcoplasmic reticulum Ca2+ channel/ryanodine receptor. Modulation by endogenous effectors, drugs, and disease states.
      ,
      • Lee E.H.
      Ca2+ channels and skeletal muscle diseases.
      ,
      • Lee E.H.
      • Kim do H.
      • Allen P.D.
      Interplay between intra- and extracellular calcium ions.
      ). In addition to the central theme of EC coupling, canonical-type transient receptor potential cation channel 3 (TRPC3) (which is a Ca2+ entry channel on sarcolemmal membrane) is required for the full gain of skeletal EC coupling (duration and maintenance) (
      • Lee E.H.
      • Cherednichenko G.
      • Pessah I.N.
      • Allen P.D.
      Functional coupling between TRPC3 and RyR1 regulates the expressions of key triadic proteins.
      ). Collaterally, channels mediating store-operated Ca2+ entry (SOCE) (
      • Liou J.
      • Kim M.L.
      • Heo W.D.
      • Jones J.T.
      • Myers J.W.
      • Ferrell Jr., J.E.
      • Meyer T.
      STIM is a Ca2+ sensor essential for Ca2+ store depletion-triggered Ca2+ influx.
      ,
      • Zhang S.L.
      • Yu Y.
      • Roos J.
      • Kozak J.A.
      • Deerinck T.J.
      • Ellisman M.H.
      • Stauderman K.A.
      • Cahalan M.D.
      STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane.
      ) are needed for the sustained presence of a certain concentration of myoplasmic Ca2+ ions in skeletal muscle cells: for example, Orai1, TRPC1, and TRPC4 (
      • Kurebayashi N.
      • Ogawa Y.
      Depletion of Ca2+ in the sarcoplasmic reticulum stimulates Ca2+ entry into mouse skeletal muscle fibres.
      ,
      • Li H.
      • Ding X.
      • Lopez J.R.
      • Takeshima H.
      • Ma J.
      • Allen P.D.
      • Eltit J.M.
      Impaired Orai1-mediated resting Ca2+ entry reduces the cytosolic [Ca2+] and sarcoplasmic reticulum Ca2+ loading in quiescent junctophilin 1 knock-out myotubes.
      ,
      • Lyfenko A.D.
      • Dirksen R.T.
      Differential dependence of store-operated and excitation-coupled Ca2+ entry in skeletal muscle on STIM1 and Orail.
      ,
      • Stiber J.
      • Hawkins A.
      • Zhang Z.S.
      • Wang S.
      • Burch J.
      • Graham V.
      • Ward C.C.
      • Seth M.
      • Finch E.
      • Malouf N.
      • Williams R.S.
      • Eu J.P.
      • Rosenberg P.
      STIM1 signaling controls store-operated calcium entry required for development and contractile function in skeletal muscle.
      ,
      • Vandebrouck C.
      • Martin D.
      • Colson-Van Schoor M.
      • Debaix H.
      • Gailly P.
      Involvement of TRPC in the abnormal calcium influx observed in dystrophic (mdx) mouse skeletal muscle fibers.
      ). Junctional membrane complexes (JMC), which are known as diad or triad junctions in striated muscle and where t-tubules and the SR membranes are juxtaposed, provide the structural context for proper arrangement of the Ca2+ channels mentioned above and for functionally efficient couplings among the Ca2+ channels (
      • Takeshima H.
      • Komazaki S.
      • Nishi M.
      • Iino M.
      • Kangawa K.
      Junctophilins, a novel family of junctional membrane complex proteins.
      ,
      • Ito K.
      • Komazaki S.
      • Sasamoto K.
      • Yoshida M.
      • Nishi M.
      • Kitamura K.
      • Takeshima H.
      Deficiency of triad junction and contraction in mutant skeletal muscle lacking junctophilin type 1.
      ).
      Junctophilins (JPs) contribute to the formation of JMC in excitable cells, including muscle cells, by interacting with both plasma and endoplasmic reticulum membranes (in muscle cells, t-tubule membranes via their N-terminal MORN motifs (highly conserved membrane occupation and recognition nexus) and SR membranes via the C-terminal transmembrane domain) (
      • Takeshima H.
      • Komazaki S.
      • Nishi M.
      • Iino M.
      • Kangawa K.
      Junctophilins, a novel family of junctional membrane complex proteins.
      ,
      • Ito K.
      • Komazaki S.
      • Sasamoto K.
      • Yoshida M.
      • Nishi M.
      • Kitamura K.
      • Takeshima H.
      Deficiency of triad junction and contraction in mutant skeletal muscle lacking junctophilin type 1.
      ,
      • Yamazaki D.
      • Yamazaki T.
      • Takeshima H.
      New molecular components supporting ryanodine receptor-mediated Ca2+ release. Roles of junctophilin and TRIC channel in embryonic cardiomyocytes.
      ,
      • Garbino A.
      • van Oort R.J.
      • Dixit S.S.
      • Landstrom A.P.
      • Ackerman M.J.
      • Wehrens X.H.
      Molecular evolution of the junctophilin gene family.
      ). Thus far, four JP subtypes have been identified: JP1 in skeletal muscle; JP2 abundantly in all muscle types (skeletal, cardiac, and smooth muscles); and JP3 and JP4 in the brain (
      • Yamazaki D.
      • Yamazaki T.
      • Takeshima H.
      New molecular components supporting ryanodine receptor-mediated Ca2+ release. Roles of junctophilin and TRIC channel in embryonic cardiomyocytes.
      ,
      • Nishi M.
      • Mizushima A.
      • Nakagawara K.
      • Takeshima H.
      Characterization of human junctophilin subtype genes.
      ,
      • Nishi M.
      • Sakagami H.
      • Komazaki S.
      • Kondo H.
      • Takeshima H.
      Coexpression of junctophilin type 3 and type 4 in brain.
      ). JP1 or JP2 knock-out in mice induces disorganized JMC and disrupted Ca2+ homeostasis in skeletal muscle or cardiomyocytes, and finally neonatal or embryonic death, respectively (
      • Takeshima H.
      • Komazaki S.
      • Nishi M.
      • Iino M.
      • Kangawa K.
      Junctophilins, a novel family of junctional membrane complex proteins.
      ,
      • Ito K.
      • Komazaki S.
      • Sasamoto K.
      • Yoshida M.
      • Nishi M.
      • Kitamura K.
      • Takeshima H.
      Deficiency of triad junction and contraction in mutant skeletal muscle lacking junctophilin type 1.
      ,
      • van Oort R.J.
      • Garbino A.
      • Wang W.
      • Dixit S.S.
      • Landstrom A.P.
      • Gaur N.
      • De Almeida A.C.
      • Skapura D.G.
      • Rudy Y.
      • Burns A.R.
      • Ackerman M.J.
      • Wehrens X.H.
      Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.
      ). JP1 and JP2 knockdown in mouse skeletal muscle fibers leads to decreases in intracellular Ca2+ release and SOCE and the disorganization of JMC (
      • Hirata Y.
      • Brotto M.
      • Weisleder N.
      • Chu Y.
      • Lin P.
      • Zhao X.
      • Thornton A.
      • Komazaki S.
      • Takeshima H.
      • Ma J.
      • Pan Z.
      Uncoupling store-operated Ca2+ entry and altered Ca2+ release from sarcoplasmic reticulum through silencing of junctophilin genes.
      ). TRPC3 knockdown in mouse skeletal myotubes involves an increase in JP1 expression and a decrease in Ca2+ transients from the SR (
      • Lee E.H.
      • Cherednichenko G.
      • Pessah I.N.
      • Allen P.D.
      Functional coupling between TRPC3 and RyR1 regulates the expressions of key triadic proteins.
      ), and the N-terminal region of JP2 (amino acids 143–234) interacts with TRPC3 in skeletal myotubes (
      • Woo J.S.
      • Kim do H.
      • Allen P.D.
      • Lee E.H.
      TRPC3-interacting triadic proteins in skeletal muscle.
      ,
      • Woo J.S.
      • Hwang J.H.
      • Ko J.K.
      • Kim do H.
      • Ma J.
      • Lee E.H.
      Glutamate at position 227 of junctophilin-2 is involved in binding to TRPC3.
      ). In the case of the neuronal JP isoforms (JP3 and JP4), the only information that has been reported involves a mouse model for neurodegenerative Huntington disease-like 2 disorder that showed a decrease in JP3 expression due to changes in the genetic level (
      • Wilburn B.
      • Rudnicki D.D.
      • Zhao J.
      • Weitz T.M.
      • Cheng Y.
      • Gu X.
      • Greiner E.
      • Park C.S.
      • Wang N.
      • Sopher B.L.
      • La Spada A.R.
      • Osmand A.
      • Margolis R.L.
      • Sun Y.E.
      • Yang X.W.
      An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington disease-like 2 mice.
      ).
      Hypertrophic cardiomyopathy (HCM) in humans, a significant cause of sudden cardiac death, is a genetic disorder related to mutations of muscle genes such as those encoding actin, myosin, tropomyosin, troponin, Z-disc proteins, and others (
      • Maron B.J.
      Hypertrophic cardiomyopathy. A systematic review.
      ). Down-regulation of JP2 has been observed in hypertrophic and dilated cardiomyopathic mouse models (
      • Minamisawa S.
      • Oshikawa J.
      • Takeshima H.
      • Hoshijima M.
      • Wang Y.
      • Chien K.R.
      • Ishikawa Y.
      • Matsuoka R.
      Junctophilin type 2 is associated with caveolin-3 and is down-regulated in the hypertrophic and dilated cardiomyopathies.
      ), in a pressure overload-induced cardiac hypertrophic rat model (
      • Xu M.
      • Zhou P.
      • Xu S.M.
      • Liu Y.
      • Feng X.
      • Bai S.H.
      • Bai Y.
      • Hao X.M.
      • Han Q.
      • Zhang Y.
      • Wang S.Q.
      Intermolecular failure of L-type Ca2+ channel and ryanodine receptor signaling in hypertrophy.
      ), and over the progression of hypertrophy into heart failure in a rat model (
      • Wei S.
      • Guo A.
      • Chen B.
      • Kutschke W.
      • Xie Y.P.
      • Zimmerman K.
      • Weiss R.M.
      • Anderson M.E.
      • Cheng H.
      • Song L.S.
      T-tubule remodeling during transition from hypertrophy to heart failure.
      ). Indeed, five JP2 single mutants (S101R, Y141H, S165F, R436C, and G505S) have been found in HCM patients (
      • Landstrom A.P.
      • Weisleder N.
      • Batalden K.B.
      • Bos J.M.
      • Tester D.J.
      • Ommen S.R.
      • Wehrens X.H.
      • Claycomb W.C.
      • Ko J.K.
      • Hwang M.
      • Pan Z.
      • Ma J.
      • Ackerman M.J.
      Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.
      ,
      • Matsushita Y.
      • Furukawa T.
      • Kasanuki H.
      • Nishibatake M.
      • Kurihara Y.
      • Ikeda A.
      • Kamatani N.
      • Takeshima H.
      • Matsuoka R.
      Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy.
      ), which strongly supports the idea that JP2 is one of the HCM-related proteins. Among the five mutants of JP2, Y141H and S165F significantly disrupt Ca2+ signaling when expressed in HL-1 atrial cardiomyocytes (
      • Landstrom A.P.
      • Weisleder N.
      • Batalden K.B.
      • Bos J.M.
      • Tester D.J.
      • Ommen S.R.
      • Wehrens X.H.
      • Claycomb W.C.
      • Ko J.K.
      • Hwang M.
      • Pan Z.
      • Ma J.
      • Ackerman M.J.
      Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.
      ). In mouse skeletal myotubes, S165F also induced hypertrophy and a reduced gain in EC coupling, which is related to the phosphorylation of S165F by protein kinase C (PKC) (
      • Woo J.S.
      • Hwang J.H.
      • Ko J.K.
      • Weisleder N.
      • Kim do H.
      • Ma J.
      • Lee E.H.
      S165F mutation of junctophilin 2 affects Ca2+ signaling in skeletal muscle.
      ). However, the effect(s) of the four other human HCM-related JP mutants on skeletal muscle have not been addressed, although JP2 is an abundant protein in both skeletal and cardiac muscles. Therefore, in the present study, Y141H, a JP2 mutant associated with human HCM and one of two mutants causing severely disrupted Ca2+ signaling in cardiomyocytes, was expressed in mouse skeletal myotubes to examine the effect(s) of Y141H on skeletal muscle function and Ca2+ signaling.

      Acknowledgments

      We acknowledge the help of Hong Lim Kim (Laboratory of Electron Microscope, Integrative Research Support Center, The Catholic University of Korea) for great expertise in TEM observations.

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