Structure, Function, and Regulation of the Junctophilin Family

Literature Cited

1. 1.

   Dai S, Hall DD, Hell JW. 2009. Supramolecular assemblies and localized regulation of voltage-gated ion channels. Physiol. Rev. 89:411–52
   [Google Scholar]
2. 2.

   Bravo-Sagua R, Parra V, Muñoz-Cordova F, Sanchez-Aguilera P, Garrido V et al. 2020. Sarcoplasmic reticulum and calcium signaling in muscle cells: homeostasis and disease. Int. Rev. Cell Mol. Biol. 350:197–264
   [Google Scholar]
3. 3.

   Chen YJ, Quintanilla CG, Liou J. 2019. Recent insights into mammalian ER-PM junctions. Curr. Opin. Cell Biol. 57:99–105
   [Google Scholar]
4. 4.

   Porter KR, Palade GE. 1957. Studies on the endoplasmic reticulum. III. Its form and distribution in striated muscle cells. J. Biophys. Biochem. Cytol. 3:269–300
   [Google Scholar]
5. 5.

   Rosenbluth J. 1962. Subsurface cisterns and their relationship to the neuronal plasma membrane. J. Cell Biol. 13:405–21
   [Google Scholar]
6. 6.

   Henkart M, Landis DM, Reese TS. 1976. Similarity of junctions between plasma membranes and endoplasmic reticulum in muscle and neurons. J. Cell Biol. 70:338–47
   [Google Scholar]
7. 7.

   Chang CL, Chen YJ, Liou J. 2017. ER-plasma membrane junctions: Why and how do we study them?. Biochim. Biophys. Acta Mol. Cell Res. 1864:1494–506
   [Google Scholar]
8. 8.

   Franzini-Armstrong C, Protasi F, Ramesh V. 1999. Shape, size, and distribution of Ca²⁺ release units and couplons in skeletal and cardiac muscles. Biophys. J. 77:1528–39
   [Google Scholar]
9. 9.

   Hayashi T, Martone ME, Yu Z, Thor A, Doi M et al. 2009. Three-dimensional electron microscopy reveals new details of membrane systems for Ca²⁺ signaling in the heart. J. Cell Sci. 122:1005–13
   [Google Scholar]
10. 10.

    Takeshima H, Hoshijima M, Song LS. 2015. Ca²⁺ microdomains organized by junctophilins. Cell Calcium 58:349–56
    [Google Scholar]
11. 11.

    Wang SQ, Wei C, Zhao G, Brochet DX, Shen J et al. 2004. Imaging microdomain Ca²⁺ in muscle cells. Circ. Res. 94:1011–22
    [Google Scholar]
12. 12.

    Williams GS, Chikando AC, Tuan HT, Sobie EA, Lederer WJ, Jafri MS. 2011. Dynamics of calcium sparks and calcium leak in the heart. Biophys. J. 101:1287–96
    [Google Scholar]
13. 13.

    Rios E. 2018. Calcium-induced release of calcium in muscle: 50 years of work and the emerging consensus. J. Gen. Physiol. 150:521–37
    [Google Scholar]
14. 14.

    Song LS, Sham JS, Stern MD, Lakatta EG, Cheng H. 1998. Direct measurement of SR release flux by tracking ‘Ca²⁺ spikes’ in rat cardiac myocytes. J. Physiol. 512:Part 3677–91
    [Google Scholar]
15. 15.

    Song LS, Wang SQ, Xiao RP, Spurgeon H, Lakatta EG, Cheng H. 2001. β-Adrenergic stimulation synchronizes intracellular Ca²⁺ release during excitation-contraction coupling in cardiac myocytes. Circ. Res. 88:794–801
    [Google Scholar]
16. 16.

    Zhao X, Yamazaki D, Kakizawa S, Pan Z, Takeshima H, Ma J. 2011. Molecular architecture of Ca²⁺ signaling control in muscle and heart cells. Channels 5:391–96
    [Google Scholar]
17. 17.

    Takeshima H, Komazaki S, Nishi M, Iino M, Kangawa K. 2000. Junctophilins: a novel family of junctional membrane complex proteins. Mol. Cell 6:11–22
    [Google Scholar]
18. 18.

    Nishi M, Sakagami H, Komazaki S, Kondo H, Takeshima H. 2003. Coexpression of junctophilin type 3 and type 4 in brain. Brain Res. Mol. Brain Res. 118:102–10
    [Google Scholar]
19. 19.

    Nishi M, Mizushima A, Nakagawara K, Takeshima H. 2000. Characterization of human junctophilin subtype genes. Biochem. Biophys. Res. Commun. 273:920–27
    [Google Scholar]
20. 20.

    Komazaki S, Ito K, Takeshima H, Nakamura H. 2002. Deficiency of triad formation in developing skeletal muscle cells lacking junctophilin type 1. FEBS Lett. 524:225–29
    [Google Scholar]
21. 21.

    Ito K, Komazaki S, Sasamoto K, Yoshida M, Nishi M et al. 2001. Deficiency of triad junction and contraction in mutant skeletal muscle lacking junctophilin type 1. J. Cell Biol. 154:1059–67
    [Google Scholar]
22. 22.

    Landstrom AP, Kellen CA, Dixit SS, van Oort RJ, Garbino A et al. 2011. Junctophilin-2 expression silencing causes cardiocyte hypertrophy and abnormal intracellular calcium-handling. Circ. Heart Fail. 4:214–23
    [Google Scholar]
23. 23.

    Hotta S, Morimura K, Ohya S, Muraki K, Takeshima H, Imaizumi Y. 2007. Ryanodine receptor type 2 deficiency changes excitation-contraction coupling and membrane potential in urinary bladder smooth muscle. J. Physiol. 582:489–506
    [Google Scholar]
24. 24.

    Pritchard HAT, Griffin CS, Yamasaki E, Thakore P, Lane C et al. 2019. Nanoscale coupling of junctophilin-2 and ryanodine receptors regulates vascular smooth muscle cell contractility. PNAS 116:21874–81
    [Google Scholar]
25. 25.

    Saeki T, Suzuki Y, Yamamura H, Takeshima H, Imaizumi Y. 2019. A junctophilin-caveolin interaction enables efficient coupling between ryanodine receptors and BK_Ca channels in the Ca²⁺ microdomain of vascular smooth muscle. J. Biol. Chem. 294:13093–105
    [Google Scholar]
26. 26.

    Ko JK, Choi KH, Zhao X, Komazaki S, Pan Z et al. 2011. A versatile single-plasmid system for tissue-specific and inducible control of gene expression in transgenic mice. FASEB J. 25:2638–49
    [Google Scholar]
27. 27.

    Nishi M, Hashimoto K, Kuriyama K, Komazaki S, Kano M et al. 2002. Motor discoordination in mutant mice lacking junctophilin type 3. Biochem. Biophys. Res. Commun. 292:318–24
    [Google Scholar]
28. 28.

    Li L, Pan ZF, Huang X, Wu BW, Li T et al. 2016. Junctophilin 3 expresses in pancreatic beta cells and is required for glucose-stimulated insulin secretion. Cell Death. Dis. 7:e2275
    [Google Scholar]
29. 29.

    Hu X, Kuang Y, Li L, Tang H, Shi Q et al. 2017. Epigenomic and functional characterization of junctophilin 3 (JPH3) as a novel tumor suppressor being frequently inactivated by promoter CpG methylation in digestive cancers. Theranostics 7:2150–63
    [Google Scholar]
30. 30.

    Crossman DJ, Ruygrok PN, Soeller C, Cannell MB. 2011. Changes in the organization of excitation-contraction coupling structures in failing human heart. PLOS ONE 6:e17901
    [Google Scholar]
31. 31.

    Lyon AR, MacLeod KT, Zhang Y, Garcia E, Kanda GK et al. 2009. Loss of T-tubules and other changes to surface topography in ventricular myocytes from failing human and rat heart. PNAS 106:6854–59
    [Google Scholar]
32. 32.

    Chen B, Li Y, Jiang S, Xie YP, Guo A et al. 2012. β-Adrenergic receptor antagonists ameliorate myocyte T-tubule remodeling following myocardial infarction. FASEB J. 26:2531–37
    [Google Scholar]
33. 33.

    Heinzel FR, Bito V, Biesmans L, Wu M, Detre E et al. 2008. Remodeling of T-tubules and reduced synchrony of Ca²⁺ release in myocytes from chronically ischemic myocardium. Circ. Res. 102:338–46
    [Google Scholar]
34. 34.

    Louch WE, Mork HK, Sexton J, Stromme TA, Laake P et al. 2006. T-tubule disorganization and reduced synchrony of Ca²⁺ release in murine cardiomyocytes following myocardial infarction. J. Physiol. 574:519–33
    [Google Scholar]
35. 35.

    Song LS, Sobie EA, McCulle S, Lederer WJ, Balke CW, Cheng H. 2006. Orphaned ryanodine receptors in the failing heart. PNAS 103:4305–10
    [Google Scholar]
36. 36.

    Wu CY, Jia Z, Wang W, Ballou LM, Jiang YP et al. 2011. PI3Ks maintain the structural integrity of T-tubules in cardiac myocytes. PLOS ONE 6:e24404
    [Google Scholar]
37. 37.

    Wu HD, Xu M, Li RC, Guo L, Lai YS et al. 2012. Ultrastructural remodelling of Ca²⁺ signalling apparatus in failing heart cells. Cardiovasc. Res. 95:430–38
    [Google Scholar]
38. 38.

    Xu M, Wu HD, Li RC, Zhang HB, Wang M et al. 2012. Mir-24 regulates junctophilin-2 expression in cardiomyocytes. Circ. Res. 111:837–41
    [Google Scholar]
39. 39.

    Zhang HB, Li RC, Xu M, Xu SM, Lai YS et al. 2013. Ultrastructural uncoupling between T-tubules and sarcoplasmic reticulum in human heart failure. Cardiovasc. Res. 98:269–76
    [Google Scholar]
40. 40.

    Wei S, Guo A, Chen B, Kutschke W, Xie YP et al. 2010. T-tubule remodeling during transition from hypertrophy to heart failure. Circ. Res. 107:520–31
    [Google Scholar]
41. 41.

    van Oort RJ, Garbino A, Wang W, Dixit SS, Landstrom AP et al. 2011. Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice. Circulation 123:979–88
    [Google Scholar]
42. 42.

    Chen B, Guo A, Zhang C, Chen R, Zhu Y et al. 2013. Critical roles of junctophilin-2 in T-tubule and excitation-contraction coupling maturation during postnatal development. Cardiovasc. Res. 100:54–62
    [Google Scholar]
43. 43.

    Reynolds JO, Chiang DY, Wang W, Beavers DL, Dixit SS et al. 2013. Junctophilin-2 is necessary for T-tubule maturation during mouse heart development. Cardiovasc. Res. 100:44–53
    [Google Scholar]
44. 44.

    Caldwell JL, Smith CE, Taylor RF, Kitmitto A, Eisner DA et al. 2014. Dependence of cardiac transverse tubules on the BAR domain protein amphiphysin II (BIN-1). Circ. Res. 115:986–96
    [Google Scholar]
45. 45.

    Brandenburg S, Pawlowitz J, Eikenbusch B, Peper J, Kohl T et al. 2019. Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis. JCI Insight 4:e127116
    [Google Scholar]
46. 46.

    Ziman AP, Gomez-Viquez NL, Bloch RJ, Lederer WJ. 2010. Excitation-contraction coupling changes during postnatal cardiac development. J. Mol. Cell. Cardiol. 48:379–86
    [Google Scholar]
47. 47.

    Han J, Wu H, Wang Q, Wang S. 2013. Morphogenesis of T-tubules in heart cells: the role of junctophilin-2. Sci. China Life Sci. 56:647–52
    [Google Scholar]
48. 48.

    Liu C, Spinozzi S, Chen JY, Fang X, Feng W et al. 2019. Nexilin is a new component of junctional membrane complexes required for cardiac T-tubule formation. Circulation 140:55–66
    [Google Scholar]
49. 49.

    Zhang C, Chen B, Guo A, Zhu Y, Miller JD et al. 2014. Microtubule-mediated defects in junctophilin-2 trafficking contribute to myocyte transverse-tubule remodeling and Ca²⁺ handling dysfunction in heart failure. Circulation 129:1742–50
    [Google Scholar]
50. 50.

    Prins KW, Asp ML, Zhang H, Wang W, Metzger JM. 2016. Microtubule-mediated misregulation of junctophilin-2 underlies T-tubule disruptions and calcium mishandling in mdx mice. JACC Basic Transl. Sci. 1:122–30
    [Google Scholar]
51. 51.

    Prins KW, Tian L, Wu D, Thenappan T, Metzger JM, Archer SL. 2017. Colchicine depolymerizes microtubules, increases junctophilin-2, and improves right ventricular function in experimental pulmonary arterial hypertension. J. Am. Heart Assoc. 6:e006195
    [Google Scholar]
52. 52.

    Guo A, Zhang X, Iyer VR, Chen B, Zhang C et al. 2014. Overexpression of junctophilin-2 does not enhance baseline function but attenuates heart failure development after cardiac stress. PNAS 111:12240–45
    [Google Scholar]
53. 53.

    Jayasinghe ID, Baddeley D, Kong CH, Wehrens XH, Cannell MB, Soeller C. 2012. Nanoscale organization of junctophilin-2 and ryanodine receptors within peripheral couplings of rat ventricular cardiomyocytes. Biophys. J. 102:L19–21
    [Google Scholar]
54. 54.

    Hou Y, Jayasinghe I, Crossman DJ, Baddeley D, Soeller C. 2015. Nanoscale analysis of ryanodine receptor clusters in dyadic couplings of rat cardiac myocytes. J. Mol. Cell. Cardiol. 80:45–55
    [Google Scholar]
55. 55.

    Jayasinghe I, Clowsley AH, Lin R, Lutz T, Harrison C et al. 2018. True molecular scale visualization of variable clustering properties of ryanodine receptors. Cell Rep. 22:557–67
    [Google Scholar]
56. 56.

    Munro ML, Jayasinghe ID, Wang Q, Quick A, Wang W et al. 2016. Junctophilin-2 in the nanoscale organisation and functional signalling of ryanodine receptor clusters in cardiomyocytes. J. Cell Sci. 129:4388–98
    [Google Scholar]
57. 57.

    Calpena E, Lopez Del Amo V, Chakraborty M, Llamusi B, Artero R et al. 2018. The Drosophila junctophilin gene is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway. Dis. Models Mech. 11:dmm029082
    [Google Scholar]
58. 58.

    Nakada T, Kashihara T, Komatsu M, Kojima K, Takeshita T, Yamada M. 2018. Physical interaction of junctophilin and the Ca_V1.1 C terminus is crucial for skeletal muscle contraction. PNAS 115:4507–12
    [Google Scholar]
59. 59.

    Phimister AJ, Lango J, Lee EH, Ernst-Russell MA, Takeshima H et al. 2007. Conformation-dependent stability of junctophilin 1 (JP1) and ryanodine receptor type 1 (RyR1) channel complex is mediated by their hyper-reactive thiols. J. Biol. Chem. 282:8667–77
    [Google Scholar]
60. 60.

    Perni S, Lavorato M, Beam KG. 2017. De novo reconstitution reveals the proteins required for skeletal muscle voltage-induced Ca²⁺ release. PNAS 114:13822–27
    [Google Scholar]
61. 61.

    Perni S, Beam K. 2022. Junctophilins 1, 2, and 3 all support voltage-induced Ca²⁺ release despite considerable divergence. J. Gen. Physiol. 154:e202113024
    [Google Scholar]
62. 62.

    Hirata Y, Brotto M, Weisleder N, Chu Y, Lin P et al. 2006. Uncoupling store-operated Ca²⁺ entry and altered Ca²⁺ release from sarcoplasmic reticulum through silencing of junctophilin genes. Biophys. J. 90:4418–27
    [Google Scholar]
63. 63.

    Li H, Ding X, Lopez JR, Takeshima H, Ma J et al. 2010. Impaired Orai1-mediated resting Ca²⁺ entry reduces the cytosolic [Ca²⁺] and sarcoplasmic reticulum Ca²⁺ loading in quiescent junctophilin 1 knock-out myotubes. J. Biol. Chem. 285:39171–79
    [Google Scholar]
64. 64.

    Lee EH, Cherednichenko G, Pessah IN, Allen PD. 2006. Functional coupling between TRPC3 and RyR1 regulates the expressions of key triadic proteins. J. Biol. Chem. 281:10042–48
    [Google Scholar]
65. 65.

    Woo JS, Hwang JH, Ko JK, Kim DH, Ma J, Lee EH. 2009. Glutamate at position 227 of junctophilin-2 is involved in binding to TRPC3. Mol. Cell. Biochem. 328:25–32
    [Google Scholar]
66. 66.

    Komazaki S, Nishi M, Takeshima H. 2003. Abnormal junctional membrane structures in cardiac myocytes expressing ectopic junctophilin type 1. FEBS Lett. 542:69–73
    [Google Scholar]
67. 67.

    Moriguchi S, Nishi M, Komazaki S, Sakagami H, Miyazaki T et al. 2006. Functional uncoupling between Ca²⁺ release and afterhyperpolarization in mutant hippocampal neurons lacking junctophilins. PNAS 103:10811–16
    [Google Scholar]
68. 68.

    Seixas AI, Holmes SE, Takeshima H, Pavlovich A, Sachs N et al. 2012. Loss of junctophilin-3 contributes to Huntington disease-like 2 pathogenesis. Ann. Neurol. 71:245–57
    [Google Scholar]
69. 69.

    Kakizawa S, Kishimoto Y, Hashimoto K, Miyazaki T, Furutani K et al. 2007. Junctophilin-mediated channel crosstalk essential for cerebellar synaptic plasticity. EMBO J. 26:1924–33
    [Google Scholar]
70. 70.

    Sahu G, Wazen RM, Colarusso P, Chen SRW, Zamponi GW, Turner RW. 2019. Junctophilin proteins tether a Cav1-RyR2-KCa3.1 tripartite complex to regulate neuronal excitability. Cell Rep. 28:2427–42.e6
    [Google Scholar]
71. 71.

    Perni S, Beam K. 2021. Neuronal junctophilins recruit specific CaV and RyR isoforms to ER-PM junctions and functionally alter Ca_V2.1 and Ca_V2.2. eLife 10:e64249
    [Google Scholar]
72. 72.

    Hogea A, Shah S, Jones F, Carver CM, Hao H et al. 2021. Junctophilin-4 facilitates inflammatory signaling at plasma membrane-endoplasmic reticulum junctions in sensory neurons. J. Physiol. 599:2103–23
    [Google Scholar]
73. 73.

    Woo JS, Srikanth S, Nishi M, Ping P, Takeshima H, Gwack Y. 2016. Junctophilin-4, a component of the endoplasmic reticulum-plasma membrane junctions, regulates Ca²⁺ dynamics in T cells. PNAS 113:2762–67
    [Google Scholar]
74. 74.

    Zhou J, Liu H, Lin Y, Zhao J. 2022. Membrane occupation and recognition nexus (MORN) motif controls protein localization and function. FEBS Lett. 596:1839–50
    [Google Scholar]
75. 75.

    Garbino A, van Oort RJ, Dixit SS, Landstrom AP, Ackerman MJ, Wehrens XH. 2009. Molecular evolution of the junctophilin gene family. Physiol. Genom. 37:175–86
    [Google Scholar]
76. 76.

    Li J, Liu H, Raval MH, Wan J, Yengo CM et al. 2019. Structure of the MORN4/Myo3a tail complex reveals MORN repeats as protein binding modules. Structure 27:1366–74
    [Google Scholar]
77. 77.

    Liu H, Li Z, Yang Q, Liu W, Wan J et al. 2019. Substrate docking-mediated specific and efficient lysine methylation by the SET domain-containing histone methyltransferase SETD7. J. Biol. Chem. 294:13355–65
    [Google Scholar]
78. 78.

    Yang ZF, Panwar P, McFarlane CR, Tuinte WE, Campiglio M, Van Petegem F. 2022. Structures of the junctophilin/voltage-gated calcium channel interface reveal hot spot for cardiomyopathy mutations. PNAS 119:e2120416119
    [Google Scholar]
79. 79.

    Fan HK, Luo TX, Zhao WD, Mu YH, Yang Y et al. 2018. Functional interaction of Junctophilin 2 with small- conductance Ca²⁺-activated potassium channel subtype 2(SK2) in mouse cardiac myocytes. Acta Physiol. 222:e12986
    [Google Scholar]
80. 80.

    Kakizawa S, Moriguchi S, Ikeda A, Iino M, Takeshima H. 2008. Functional crosstalk between cell-surface and intracellular channels mediated by junctophilins essential for neuronal functions. Cerebellum 7:385–91
    [Google Scholar]
81. 81.

    Bennett HJ, Davenport JB, Collins RF, Trafford AW, Pinali C, Kitmitto A. 2013. Human junctophilin-2 undergoes a structural rearrangement upon binding PtdIns(3,4,5)P₃ and the S101R mutation identified in hypertrophic cardiomyopathy obviates this response. Biochem. J. 456:205–17
    [Google Scholar]
82. 82.

    Rossi D, Scarcella AM, Liguori E, Lorenzini S, Pierantozzi E et al. 2019. Molecular determinants of homo- and heteromeric interactions of Junctophilin-1 at triads in adult skeletal muscle fibers. PNAS 116:15716–24
    [Google Scholar]
83. 83.

    Golini L, Chouabe C, Berthier C, Cusimano V, Fornaro M et al. 2011. Junctophilin 1 and 2 proteins interact with the L-type Ca²⁺ channel dihydropyridine receptors (DHPRs) in skeletal muscle. J. Biol. Chem. 286:43717–25
    [Google Scholar]
84. 84.

    Gross P, Johnson J, Romero CM, Eaton DM, Poulet C et al. 2020. Interaction of the joining region in junctophilin-2 with the L-type Ca²⁺ channel is pivotal for cardiac dyad assembly and intracellular Ca²⁺ dynamics. Circ. Res. 128:92–114
    [Google Scholar]
85. 85.

    Wang W, Landstrom AP, Wang Q, Munro ML, Beavers D et al. 2014. Reduced junctional Na⁺/Ca²⁺-exchanger activity contributes to sarcoplasmic reticulum Ca²⁺ leak in junctophilin-2-deficient mice. Am. J. Physiol. Heart Circ. Physiol. 307:H1317–26
    [Google Scholar]
86. 86.

    Beavers DL, Wang W, Ather S, Voigt N, Garbino A et al. 2013. Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization. J. Am. Coll. Cardiol. 62:2010–19
    [Google Scholar]
87. 87.

    Minamisawa S, Oshikawa J, Takeshima H, Hoshijima M, Wang Y et al. 2004. Junctophilin type 2 is associated with caveolin-3 and is down-regulated in the hypertrophic and dilated cardiomyopathies. Biochem. Biophys. Res. Commun. 325:852–56
    [Google Scholar]
88. 88.

    Poulet C, Sanchez-Alonso J, Swiatlowska P, Mouy F, Lucarelli C et al. 2020. Junctophilin-2 tethers T-tubules and recruits functional L-type calcium channels to lipid rafts in adult cardiomyocytes. Cardiovasc. Res. 117:149–61
    [Google Scholar]
89. 89.

    Bergdahl A, Sward K. 2004. Caveolae-associated signalling in smooth muscle. Can. J. Physiol. Pharmacol. 82:289–99
    [Google Scholar]
90. 90.

    Jiang M, Zhang M, Howren M, Wang Y, Tan A et al. 2016. JPH-2 interacts with Cai-handling proteins and ion channels in dyads: contribution to premature ventricular contraction-induced cardiomyopathy. Heart Rhythm 13:743–52
    [Google Scholar]
91. 91.

    Mathiesen SB, Lunde M, Stensland M, Martinsen M, Nyman TA et al. 2020. The cardiac syndecan-2 interactome. Front. Cell Dev. Biol. 8:792
    [Google Scholar]
92. 92.

    Hennessey JA, Wei EQ, Pitt GS. 2013. Fibroblast growth factor homologous factors modulate cardiac calcium channels. Circ. Res. 113:381–88
    [Google Scholar]
93. 93.

    Hennessey JA, Marcou CA, Wang C, Wei EQ, Wang C et al. 2013. FGF12 is a candidate Brugada syndrome locus. Heart Rhythm 10:1886–94
    [Google Scholar]
94. 94.

    Quick AP, Wang Q, Philippen LE, Barreto-Torres G, Chiang DY et al. 2017. SPEG (striated muscle preferentially expressed protein kinase) is essential for cardiac function by regulating junctional membrane complex activity. Circ. Res. 120:110–19
    [Google Scholar]
95. 95.

    Feng W, Liu C, Spinozzi S, Wang L, Evans SM, Chen J. 2020. Identifying the cardiac dyad proteome in vivo by a BioID2 knock-in strategy. Circulation 141:940–42
    [Google Scholar]
96. 96.

    Guo A, Hall D, Zhang C, Peng T, Miller JD et al. 2015. Molecular determinants of calpain-dependent cleavage of junctophilin-2 protein in cardiomyocytes. J. Biol. Chem. 290:17946–55
    [Google Scholar]
97. 97.

    Guo A, Wang Y, Chen B, Wang Y, Yuan J et al. 2018. E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator. Science 362:eaan3303
    [Google Scholar]
98. 98.

    Lahiri SK, Quick AP, Samson-Couterie B, Hulsurkar M, Elzenaar I et al. 2020. Nuclear localization of a novel calpain-2 mediated junctophilin-2 C-terminal cleavage peptide promotes cardiomyocyte remodeling. Basic Res. Cardiol. 115:49
    [Google Scholar]
99. 99.

    Jiang M, Hu J, White FKH, Williamson J, Klymchenko AS et al. 2019. S-Palmitoylation of junctophilin-2 is critical for its role in tethering the sarcoplasmic reticulum to the plasma membrane. J. Biol. Chem. 294:13487–501
    [Google Scholar]
100. 100.

     Murphy RM, Dutka TL, Horvath D, Bell JR, Delbridge LM, Lamb GD. 2013. Ca²⁺-dependent proteolysis of junctophilin-1 and junctophilin-2 in skeletal and cardiac muscle. J. Physiol. 591:719–29
     [Google Scholar]
101. 101.

     Wu CY, Chen B, Jiang YP, Jia Z, Martin DW et al. 2014. Calpain-dependent cleavage of junctophilin-2 and T-tubule remodeling in a mouse model of reversible heart failure. J. Am. Heart Assoc. 3:e000527
     [Google Scholar]
102. 102.

     Kanzaki K, Watanabe D, Kuratani M, Yamada T, Matsunaga S, Wada M. 2017. Role of calpain in eccentric contraction-induced proteolysis of Ca²⁺-regulatory proteins and force depression in rat fast-twitch skeletal muscle. J. Appl. Physiol. 122:396–405
     [Google Scholar]
103. 103.

     Wang Y, Chen B, Huang CK, Guo A, Wu J et al. 2018. Targeting calpain for heart failure therapy: implications from multiple murine models. JACC Basic Transl. Sci. 3:503–17
     [Google Scholar]
104. 104.

     Chan BYH, Roczkowsky A, Cho WJ, Poirier M, Lee TYT et al. 2019. Junctophilin-2 is a target of matrix metalloproteinase-2 in myocardial ischemia-reperfusion injury. Basic Res. Cardiol. 114:42
     [Google Scholar]
105. 105.

     Tammineni ER, Figueroa L, Manno C, Varma D, Kraeva N et al. 2023. Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation. eLife 12:e78874
     [Google Scholar]
106. 106.

     Wang J, Ciampa G, Zheng D, Shi Q, Chen B et al. 2021. Calpain-2 specifically cleaves Junctophilin-2 at the same site as Calpain-1 but with less efficacy. Biochem. J. 478:3539–53
     [Google Scholar]
107. 107.

     Weninger G, Pochechueva T, El Chami D, Luo X, Kohl T et al. 2022. Calpain cleavage of Junctophilin-2 generates a spectrum of calcium-dependent cleavage products and DNA-rich NT1-fragment domains in cardiomyocytes. Sci. Rep. 12:10387
     [Google Scholar]
108. 108.

     Essandoh K, Subramani A, Ferro OA, Teuber JP, Koripella S, Brody MJ. 2023. zDHHC9 regulates cardiomyocyte Rab3a activity and atrial natriuretic peptide secretion through palmitoylation of Rab3gap1. JACC Basic Transl. Sci. 8:518–42
     [Google Scholar]
109. 109.

     Landstrom AP, Weisleder N, Batalden KB, Bos JM, Tester DJ et al. 2007. Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans. J. Mol. Cell. Cardiol. 42:1026–35
     [Google Scholar]
110. 110.

     Woo JS, Hwang JH, Ko JK, Weisleder N, Kim DH et al. 2010. S165F mutation of junctophilin 2 affects Ca²⁺ signalling in skeletal muscle. Biochem. J. 427:125–34
     [Google Scholar]
111. 111.

     Padmanabhan A, Haldar SM. 2018. Unusual transcription factor protects against heart failure. Science 362:1359–60
     [Google Scholar]
112. 112.

     Wang J, Shi Q, Wang Y, Dawson LW, Ciampa G et al. 2022. Gene therapy with the N-terminus of junctophilin-2 improves heart failure in mice. Circ. Res. 130:1306–17
     [Google Scholar]
113. 113.

     Ingles J, Goldstein J, Thaxton C, Caleshu C, Corty EW et al. 2019. Evaluating the clinical validity of hypertrophic cardiomyopathy genes. Circ. Genom. Precis. Med. 12:e002460
     [Google Scholar]
114. 114.

     Jordan E, Peterson L, Ai T, Asatryan B, Bronicki L et al. 2021. An evidence-based assessment of genes in dilated cardiomyopathy. Circulation 144:7–19
     [Google Scholar]
115. 115.

     Parker LE, Kramer RJ, Kaplan S, Landstrom AP. 2023. One gene, two modes of inheritance, four diseases: a systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2. Trends Cardiovasc. Med. 33:1–10
     [Google Scholar]
116. 116.

     Pla-Martin D, Calpena E, Lupo V, Marquez C, Rivas E et al. 2015. Junctophilin-1 is a modifier gene of GDAP1-related Charcot-Marie-Tooth disease. Hum. Mol. Genet. 24:213–29
     [Google Scholar]
117. 117.

     Holmes SE, O'Hearn E, Rosenblatt A, Callahan C, Hwang HS et al. 2001. A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Nat. Genet. 29:377–78
     [Google Scholar]
118. 118.

     Wu F, Li X, Bai R, Li Y, Gao J, Lan F. 2020. Generation of a Junctophilin-2 homozygous knockout human embryonic stem cell line (WAe009-A-36) by an episomal vector-based CRISPR/Cas9 system. Stem Cell Res. 48:101930
     [Google Scholar]
119. 119.

     Guo Y, VanDusen NJ, Zhang L, Gu W, Sethi I et al. 2017. Analysis of cardiac myocyte maturation using CASAAV, a platform for rapid dissection of cardiac myocyte gene function in vivo. Circ. Res. 120:1874–88
     [Google Scholar]
120. 120.

     Reynolds JO, Quick AP, Wang Q, Beavers DL, Philippen LE et al. 2016. Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca²⁺ release. Int. J. Cardiol. 225:371–80
     [Google Scholar]
121. 121.

     Yang L, Li RC, Xiang B, Li YC, Wang LP et al. 2021. Transcriptional regulation of intermolecular Ca²⁺ signaling in hibernating ground squirrel cardiomyocytes: the myocardin-junctophilin axis. PNAS 118:e2025333118
     [Google Scholar]
122. 122.

     Hu J, Gao C, Wei C, Xue Y, Shao C et al. 2019. RBFox2-miR-34a-Jph2 axis contributes to cardiac decompensation during heart failure. PNAS 116:6172–80
     [Google Scholar]
123. 123.

     Zhang J-J, Wang L-P, Li R-C, Wang M, Huang Z-H et al. 2019. Abnormal expression of miR-331 leads to impaired heart function. Sci. Bull. 64:1011–17
     [Google Scholar]
124. 124.

     Li RC, Tao J, Guo YB, Wu HD, Liu RF et al. 2013. In vivo suppression of microRNA-24 prevents the transition toward decompensated hypertrophy in aortic-constricted mice. Circ. Res. 112:601–5
     [Google Scholar]
125. 125.

     Kanwal S, Perveen S. 2019. Association of SNP in JPH1 gene with severity of disease in Charcot Marie Tooth 2K patients. J. Pak. Med. Assoc. 69:241–43
     [Google Scholar]
126. 126.

     Sabater-Molina M, Navarro M, Garcia-Molina Saez E, Garrido I, Pascual-Figal D et al. 2016. Mutation in JPH2 cause dilated cardiomyopathy. Clin. Genet. 90:468–69
     [Google Scholar]
127. 127.

     Vanninen SUM, Leivo K, Seppala EH, Aalto-Setala K, Pitkanen O et al. 2018. Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure. PLOS ONE 13:e0203422
     [Google Scholar]
128. 128.

     Narula N, Tester DJ, Paulmichl A, Maleszewski JJ, Ackerman MJ. 2015. Post-mortem whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series. Pediatr. Cardiol. 36:768–78
     [Google Scholar]
129. 129.

     Sahlin E, Green A, Gustavsson P, Lieden A, Nordenskjold M et al. 2019. Identification of putative pathogenic single nucleotide variants (SNVs) in genes associated with heart disease in 290 cases of stillbirth. PLOS ONE 14:e0210017
     [Google Scholar]
130. 130.

     Miura A, Kondo H, Yamamoto T, Okumura Y, Nishio H. 2020. Sudden unexpected death of infantile dilated cardiomyopathy with JPH2 and PKD1 gene variants. Int. Heart J. 61:1079–83
     [Google Scholar]
131. 131.

     Neubauer J, Haas C, Bartsch C, Medeiros-Domingo A, Berger W. 2016. Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases. Int. J. Legal Med. 130:1011–21
     [Google Scholar]
132. 132.

     Quick AP, Landstrom AP, Wang Q, Beavers DL, Reynolds JO et al. 2017. Novel junctophilin-2 mutation A405S is associated with basal septal hypertrophy and diastolic dysfunction. JACC Basic Transl. Sci. 2:56–67
     [Google Scholar]
133. 133.

     Seidelmann SB, Smith E, Subrahmanyan L, Dykas D, Abou Ziki MD et al. 2017. Application of whole exome sequencing in the clinical diagnosis and management of inherited cardiovascular diseases in adults. Circ. Cardiovasc. Genet. 10:e001573
     [Google Scholar]
134. 134.

     Matsushita Y, Furukawa T, Kasanuki H, Nishibatake M, Kurihara Y et al. 2007. Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy. J. Hum. Genet. 52:543–48
     [Google Scholar]
135. 135.

     Jones EG, Mazaheri N, Maroofian R, Zamani M, Seifi T et al. 2019. Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy. Sci. Rep. 9:9038
     [Google Scholar]
136. 136.

     Stevanin G, Camuzat A, Holmes SE, Julien C, Sahloul R et al. 2002. CAG/CTG repeat expansions at the Huntington's disease-like 2 locus are rare in Huntington's disease patients. Neurology 58:965–7
     [Google Scholar]
137. 137.

     Krause A, Mitchell C, Essop F, Tager S, Temlett J et al. 2015. Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype. Am. J. Med. Genet. B Neuropsychiatr. Genet. 168:573–85
     [Google Scholar]
138. 138.

     Stevanin G, Fujigasaki H, Lebre AS, Camuzat A, Jeannequin C et al. 2003. Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes. Brain 126:1599–603
     [Google Scholar]
139. 139.

     Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A et al. 2010. A method and server for predicting damaging missense mutations. Nat. Methods 7:248–49
     [Google Scholar]
140. 140.

     Choi Y, Chan AP. 2015. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31:2745–47
     [Google Scholar]
141. 141.

     Ng PC, Henikoff S. 2003. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 31:3812–14
     [Google Scholar]
142. 142.

     Yoshida M, Sugimoto A, Ohshima Y, Takeshima H. 2001. Important role of junctophilin in nematode motor function. Biochem. Biophys. Res. Commun. 289:234–39
     [Google Scholar]