{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:35:20Z","timestamp":1760060120882,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T00:00:00Z","timestamp":1754092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiovascular disease encompasses a wide group of conditions that affect the heart and blood vessels. Of these diseases, cardiomyopathies and arrhythmias specifically have been well-studied in their relationship to cardiac dyads, nanoscopic structures that connect electrical signals to muscle contraction. The proper development and positioning of dyads is essential in excitation\u2013contraction (EC) coupling and, thus, beating of the heart. Three proteins, namely CMYA5, JPH2, and BIN1, are responsible for maintaining the dyadic cleft between the T-tubule and junctional sarcoplasmic reticulum (jSR). Various other dyadic proteins play integral roles in the primary function of the dyad\u2014translating a propagating action potential (AP) into a myocardial contraction. Ca2+, a secondary messenger in this process, acts as an allosteric activator of the sarcomere, and its cytoplasmic concentration is regulated by the dyad. Loss-of-function mutations have been shown to result in cardiomyopathies and arrhythmias. Adeno-associated virus (AAV) gene therapy with dyad components can rescue dyadic dysfunction, which results in cardiomyopathies and arrhythmias. Overall, the dyad and its components serve as essential mediators of calcium homeostasis and excitation\u2013contraction coupling in the mammalian heart and, when dysfunctional, result in significant cardiac dysfunction, arrhythmias, morbidity, and mortality.<\/jats:p>","DOI":"10.3390\/ijms26157478","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T07:45:11Z","timestamp":1754466311000},"page":"7478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Role of Dyadic Proteins in Proper Heart Function and Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Carter","family":"Liou","sequence":"first","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3065-8498","authenticated-orcid":false,"given":"Michael T.","family":"Chin","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA"},{"name":"Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1126\/science.276.5313.800","article-title":"Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure","volume":"276","author":"Valdivia","year":"1997","journal-title":"Science"},{"key":"ref_2","unstructured":"Basit, H., Brito, D., and Sharma, S. (2024, November 17). Hypertrophic Cardiomyopathy, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK430788\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/S0140-6736(16)31713-5","article-title":"Dilated cardiomyopathy","volume":"390","author":"Weintraub","year":"2017","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1038\/s41467-022-29902-4","article-title":"CMYA5 Establishes Cardiac Dyad Architecture and Positioning","volume":"13","author":"Lu","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1093\/cvr\/cvaa033","article-title":"Junctophilin-2 tethers T-tubules and recruits functional L-type calcium channels to lipid rafts in adult cardiomyocytes","volume":"117","author":"Poulet","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"ref_6","first-page":"11","article-title":"Junctophilins: A Novel Family of Junctional Membrane Complex Proteins","volume":"6","author":"Takeshima","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1038\/aps.2010.116","article-title":"Emerging role of junctophilin-2 as a regulator of calcium handling in the heart","volume":"31","author":"Garbino","year":"2010","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1161\/CIRCULATIONAHA.110.006437","article-title":"Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice","volume":"123","author":"Garbino","year":"2011","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12917","DOI":"10.1021\/bi060717k","article-title":"The crystal structure of the BAR domain from human Bin1\/amphiphysin II and its implications for molecular recognition","volume":"45","author":"Casal","year":"2006","journal-title":"Biochemistry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1126\/science.1092586","article-title":"BAR domains as sensors of membrane curvature: The amphiphysin BAR structure","volume":"303","author":"Peter","year":"2004","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"RP95397","DOI":"10.7554\/eLife.95397","article-title":"Uncovering the BIN1-SH3 interactome underpinning centronuclear myopathy","volume":"13","author":"Boglarka","year":"2024","journal-title":"eLife"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3306","DOI":"10.1172\/JCI27167","article-title":"The L-type calcium channel in the heart: The beat goes on","volume":"115","author":"Bodi","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1124\/pr.57.4.5","article-title":"International Union of Pharmacology. XLVIII. nomenclature and structure-function relationships of voltage-gated calcium channels","volume":"57","author":"Catterall","year":"2005","journal-title":"Pharmacol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1152\/jn.00486.2004","article-title":"L-Type Calcium Channels: The Low Down","volume":"92","author":"Lipscombe","year":"2004","journal-title":"J. Neurophysiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15657","DOI":"10.1073\/pnas.0604621103","article-title":"Switching off calcium-dependent inactivation in L-type calcium channels by an autoinhibitory domain","volume":"103","author":"Baumann","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/wmts.102","article-title":"L-type Ca2+ channels in heart and brain","volume":"3","author":"Striessnig","year":"2014","journal-title":"Wiley Interdiscip. Rev. Membr. Transp. Signal."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"19006","DOI":"10.1074\/jbc.M109.011296","article-title":"Structural model for dihydropyridine binding to L-type calcium channels","volume":"284","author":"Tikhonov","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bauerov\u00e1-Hlinkov\u00e1, V., Hajd\u00fachov\u00e1, D., and Bauer, J.A. (2020). Structure and Function of the Human Ryanodine Receptors and Their Association with Myopathies-Present State, Challenges, and Perspectives. Molecules, 25.","DOI":"10.3390\/molecules25184040"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1007\/s12551-018-0433-4","article-title":"Regulation of the RyR channel gating by Ca2+ and Mg2","volume":"10","author":"Laver","year":"2018","journal-title":"Biophys. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1085\/jgp.201812155","article-title":"Phosphorylation of the ryanodine receptor 2 at serine 2030 is required for a complete \u03b2-adrenergic response","volume":"151","author":"Potenza","year":"2019","journal-title":"J. Gen. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1042\/BCJ20180545","article-title":"Ca2+-dependent calmodulin binding to cardiac ryanodine receptor (RyR2) calmodulin-binding domains","volume":"476","author":"Brohus","year":"2019","journal-title":"Biochem. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jsb.2012.02.008","article-title":"Crystal structure of sarcoplasmic reticulum Ca2+-ATPase (SERCA) from bovine muscle","volume":"178","author":"Sacchetto","year":"2012","journal-title":"J. Struct. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12722","DOI":"10.1073\/pnas.1815472115","article-title":"Mechanism of the E2 to E1 transition in Ca2+ pump revealed by crystal structures of gating residue mutants","volume":"115","author":"Tsunekawa","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1093\/cvr\/cvm056","article-title":"Regulation of sarcoplasmic reticulum Ca2+ ATPase pump expression and its relevance to cardiac muscle physiology and pathology","volume":"77","author":"Periasamy","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1007\/s12471-018-1211-4","article-title":"Prevalence and cardiac phenotype of patients with a phospholamban mutation","volume":"27","author":"Hof","year":"2019","journal-title":"Neth. Heart J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1038\/nm.2897","article-title":"Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals","volume":"18","author":"Bal","year":"2012","journal-title":"Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Bal, N.C., and Periasamy, M. (2020). Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci., 375.","DOI":"10.1098\/rstb.2019.0135"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/nrm1151","article-title":"Phospholamban: A crucial regulator of cardiac contractility","volume":"4","author":"MacLennan","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.1113\/JP281579","article-title":"Increasing SERCA function promotes initiation of calcium sparks and breakup of calcium waves","volume":"599","author":"Sato","year":"2021","journal-title":"J. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1111\/j.1460-9568.1997.tb01482.x","article-title":"Na+-Ca2+Exchange Currents in Cortical Neurons: Concomitant Forward and Reverse Operation and Effect of Glutamate","volume":"9","author":"Yu","year":"1997","journal-title":"Eur. J. Neurosci."},{"key":"ref_31","first-page":"1364","article-title":"Sipido, Targeting calcium handling in arrhythmias","volume":"10","author":"Gudrun","year":"2008","journal-title":"EP Eur."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.yjmcc.2013.01.010","article-title":"The topology of the cardiac Na+\/Ca2+ exchanger, NCX1","volume":"57","author":"Ren","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6181","DOI":"10.1038\/s41467-023-41885-4","article-title":"Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1","volume":"14","author":"Xue","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1111\/j.1749-6632.1974.tb19091.x","article-title":"Experimental and theoretical examination of the flip-flop model of (Na, K)-ATPase function","volume":"242","author":"Repke","year":"1974","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1126\/science.1215759","article-title":"Structural insight into the ion-exchange mechanism of the sodium\/calcium exchanger","volume":"335","author":"Liao","year":"2012","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/978-1-4614-4756-6_14","article-title":"Regulation of sodium-calcium exchanger activity by creatine kinase","volume":"961","author":"Yang","year":"2013","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0014-5793(01)03323-3","article-title":"Evidence for cardiac sodium-calcium exchanger association with caveolin-3","volume":"511","author":"Bossuyt","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/s41551-024-01253-z","article-title":"Virally delivered CMYA5 enhances the assembly of cardiac dyads","volume":"9","author":"Lu","year":"2025","journal-title":"Nat. Biomed. Eng."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1146\/annurev-physiol-042022-014926","article-title":"Structure, Function, and Regulation of the Junctophilin Family","volume":"86","author":"Hall","year":"2023","journal-title":"Annu. Rev. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1161\/CIRCRESAHA.119.315715","article-title":"Interaction of the Joining Region in Junctophilin-2 With the L-Type Ca 2+ Channel Is Pivotal for Cardiac Dyad Assembly and Intracellular Ca2+ Dynamics","volume":"128","author":"Gross","year":"2021","journal-title":"Circ. Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Hong, T.T., Smyth, J.W., Gao, D., Chu, K.Y., Vogan, J.M., Fong, T.S., Jensen, B.C., Colecraft, H.M., and Shaw, R.M. (2010). BIN1 localizes the L-type calcium channel to cardiac T-tubules. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000312"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1161\/01.CIR.103.4.485","article-title":"Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia","volume":"103","author":"Laitinen","year":"2001","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8080","DOI":"10.1038\/s41467-024-51791-y","article-title":"Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders","volume":"15","author":"Miotto","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"323","DOI":"10.4103\/tcmj.tcmj_288_20","article-title":"The link between abnormalities of calcium handling proteins and catecholaminergic polymorphic ventricular tachycardia","volume":"33","author":"Lin","year":"2021","journal-title":"Tzu Chi Med. J."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Baltogiannis, G.G., Lysitsas, D.N., di Giovanni, G., Ciconte, G., Sieira, J., Conte, G., Kolettis, T.M., Chierchia, G.B., de Asmundis, C., and Brugada, P. (2019). CPVT: Arrhythmogenesis, Therapeutic Management, and Future Perspectives. A Brief Review of the Literature. Front. Cardiovasc. Med., 6.","DOI":"10.3389\/fcvm.2019.00092"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1161\/CIRCULATIONAHA.118.038514","article-title":"Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia by Inhibition of Ca2+\/Calmodulin-Dependent Kinase II","volume":"140","author":"Bezzerides","year":"2019","journal-title":"Circulation"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Balcazar, D., Regge, V., Santalla, M., Meyer, H., Paululat, A., Mattiazzi, A., and Ferrero, P. (2018). SERCA is critical to control the Bowditch effect in the heart. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-30638-9"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/bph.12472","article-title":"SERCA2a gene therapy in heart failure: An anti-arrhythmic positive inotrope","volume":"171","author":"Sikkel","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1161\/CIRCEP.110.961615","article-title":"SERCA2a Gene Transfer Decreases Sarcoplasmic Reticulum Calcium Leak and Reduces Ventricular Arrhythmias in a Model of Chronic Heart Failure","volume":"4","author":"Lyon","year":"2011","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1016\/S0140-6736(16)00082-9","article-title":"Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): A randomised, multinational, double-blind, placebo-controlled, phase 2b trial","volume":"387","author":"Greenberg","year":"2016","journal-title":"Lancet"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.yjmcc.2007.04.006","article-title":"Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans","volume":"42","author":"Landstrom","year":"2007","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Bazgir, F., Nau, J., Nakhaei-Rad, S., Amin, E., Wolf, M.J., Saucerman, J.J., Lorenz, K., and Ahmadian, M.R. (2023). The Microenvironment of the Pathogenesis of Cardiac Hypertrophy. Cells, 12.","DOI":"10.3390\/cells12131780"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1093\/cvr\/cvt133","article-title":"Junctophilin-2 is necessary for T-tubule maturation during mouse heart development","volume":"100","author":"Reynolds","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41572-019-0084-1","article-title":"Dilated cardiomyopathy","volume":"5","author":"Schultheiss","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1016\/j.hrthm.2014.07.020","article-title":"Prevalence and significance of rare RYR2 variants in arrhythmogenic right ventricular cardiomyopathy\/dysplasia: Results of a systematic screening","volume":"11","author":"Gandjbakhch","year":"2014","journal-title":"Heart Rhythm."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1002\/jcb.25198","article-title":"Cardiac-Specific Disruption of Bin1 in Mice Enables a Model of Stress- and Age-Associated Dilated Cardiomyopathy","volume":"116","author":"Mulgrew","year":"2015","journal-title":"J. Cell. Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.jacbts.2020.03.018","article-title":"Cardiac BIN1 Replacement Therapy Ameliorates Inotropy and Lusitropy in Heart Failure by Regulating Calcium Handling","volume":"5","author":"Gambardella","year":"2020","journal-title":"JACC Basic Transl. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7478\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:21:50Z","timestamp":1760034110000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,2]]},"references-count":57,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26157478"],"URL":"https:\/\/doi.org\/10.3390\/ijms26157478","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,8,2]]}}}