BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts.

Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE

Original Publication: [London] : Nature Pub. Group

Adaptor Proteins, Signal Transducing*/metabolism ; Adaptor Proteins, Signal Transducing*/genetics ; Aging*/metabolism ; Tumor Suppressor Proteins*/metabolism ; Tumor Suppressor Proteins*/genetics ; Myocardium*/metabolism ; Myocardium*/pathology ; Ryanodine Receptor Calcium Release Channel*/metabolism ; Ryanodine Receptor Calcium Release Channel*/genetics ; Nerve Tissue Proteins*; Animals ; Male ; Mice ; Gene Knockdown Techniques ; Endosomes/metabolism ; Calcium Channels, L-Type/metabolism ; Calcium Channels, L-Type/genetics ; Heart/physiopathology ; Mice, Inbred C57BL ; Humans ; Myocytes, Cardiac/metabolism ; Nuclear Proteins/metabolism ; Nuclear Proteins/genetics ; RNA, Small Interfering/metabolism ; RNA, Small Interfering/genetics ; Systole

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac Ca V 1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca ²⁺ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.
(© 2024. The Author(s).)

Erratum in: Nat Commun. 2024 May 23;15(1):4397. (PMID: 38782927)

Roth, G. A. et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study. J. Am. Coll. Cardiol. 76, 2982–3021 (2020). (PMID: 33309175775503810.1016/j.jacc.2020.11.010)
Dhingra, R. & Vasan, R. S. Age as a risk factor. Med Clin. North Am. 96, 87–91 (2012). (PMID: 2239125310.1016/j.mcna.2011.11.003)
Dai, D. F., Chen, T., Johnson, S. C., Szeto, H. & Rabinovitch, P. S. Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid. Redox Signal 16, 1492–1526 (2012). (PMID: 22229339332995310.1089/ars.2011.4179)
Strait, J. B. & Lakatta, E. G. Aging-associated cardiovascular changes and their relationship to heart failure. Heart Fail. Clin. 8, 143–164 (2012). (PMID: 22108734322337410.1016/j.hfc.2011.08.011)
Lakatta, E. G. & Sollott, S. J. Perspectives on mammalian cardiovascular aging: humans to molecules. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 132, 699–721 (2002). (PMID: 1209585710.1016/S1095-6433(02)00124-1)
Ferrara, N. et al. beta-adrenergic receptor responsiveness in aging heart and clinical implications. Front. Physiol. 4, 396 (2014). (PMID: 24409150388580710.3389/fphys.2013.00396)
Xiao, R. P. et al. Age-associated reductions in cardiac β1- and β2-adrenergic responses without changes in inhibitory G proteins or receptor kinases. J. Clin. Invest. 101, 1273–1282 (1998). (PMID: 950276850868110.1172/JCI1335)
Xiao, R. P., Spurgeon, H. A., O’Connor, F. & Lakatta, E. G. Age-associated changes in β-adrenergic modulation on rat cardiac excitation-contraction coupling. J. Clin. Invest. 94, 2051–2059 (1994). (PMID: 796255129464010.1172/JCI117559)
Osterrieder, W. et al. Injection of subunits of cyclic AMP-dependent protein kinase into cardiac myocytes modulates Ca2+ current. Nature 298, 576–578 (1982). (PMID: 628519910.1038/298576a0)
Hartzell, H. C., Mery, P. F., Fischmeister, R. & Szabo, G. Sympathetic regulation of cardiac calcium current is due exclusively to cAMP-dependent phosphorylation. Nature 351, 573–576 (1991). (PMID: 171078410.1038/351573a0)
Liu, G. et al. Mechanism of adrenergic Ca V 1.2 stimulation revealed by proximity proteomics. Nature 577, 695–700 (2020). (PMID: 31969708701838310.1038/s41586-020-1947-z)
Manning, J. R. et al. Rad GTPase deletion increases L-type calcium channel current leading to increased cardiac contraction. J. Am. Heart Assoc. 2, e000459 (2013). (PMID: 24334906388677710.1161/JAHA.113.000459)
Yue, D. T., Herzig, S. & Marban, E. β-adrenergic stimulation of calcium channels occurs by potentiation of high-activity gating modes. Proc. Natl Acad. Sci. USA 87, 753–757 (1990). (PMID: 16890515334410.1073/pnas.87.2.753)
Bean, B. P., Nowycky, M. C. & Tsien, R. W. Beta-adrenergic modulation of calcium channels in frog ventricular heart cells. Nature 307, 371–375 (1984). (PMID: 632000210.1038/307371a0)
Del Villar, S. G. et al. beta-Adrenergic control of sarcolemmal Ca V 1.2 abundance by small GTPase Rab proteins. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2017937118 (2021).
Ito, D. W. et al. β-adrenergic-mediated dynamic augmentation of sarcolemmal Ca V 1.2 clustering and co-operativity in ventricular myocytes. J. Physiol. 597, 2139–2162 (2019). (PMID: 30714156646246410.1113/JP277283)
Dixon, R. E., Navedo, M. F., Binder, M. D. & Santana, L. F. Mechanisms and physiological implications of cooperative gating of ion channels clusters. Physiol. Rev. https://doi.org/10.1152/physrev.00022.2021 (2021).
Fu, Y. et al. Isoproterenol promotes rapid ryanodine receptor movement to bridging integrator 1 (BIN1)-organized dyads. Circulation 133, 388–397 (2016). (PMID: 26733606472961510.1161/CIRCULATIONAHA.115.018535)
Asghari, P. et al. Cardiac ryanodine receptor distribution is dynamic and changed by auxiliary proteins and post-translational modification. Elife https://doi.org/10.7554/eLife.51602 (2020).
Dixon, R. E. Nanoscale organization, regulation, and dynamic reorganization of cardiac calcium channels. Front. Physiol. 12, 810408 (2021). (PMID: 3506926410.3389/fphys.2021.810408)
Galice, S., Xie, Y., Yang, Y., Sato, D. & Bers, D. M. Size matters: ryanodine receptor cluster size affects arrhythmogenic sarcoplasmic reticulum calcium release. J. Am. Heart Assoc. https://doi.org/10.1161/JAHA.118.008724 (2018).
Mougenot, N. et al. Cardiac adenylyl cyclase overexpression precipitates and aggravates age-related myocardial dysfunction. Cardiovasc. Res. 115, 1778–1790 (2019). (PMID: 30605506675535710.1093/cvr/cvy306)
Cataldo, A. M. et al. Endocytic pathway abnormalities precede amyloid-β deposition in sporadic Alzheimer’s disease and down syndrome: differential effects of APOE genotype and presenilin mutations. Am. J. Pathol. 157, 277–286 (2000). (PMID: 10880397185021910.1016/S0002-9440(10)64538-5)
Small, S. A., Simoes-Spassov, S., Mayeux, R. & Petsko, G. A. Endosomal traffic jams represent a pathogenic hub and therapeutic target in Alzheimer’s disease. Trends Neurosci. 40, 592–602 (2017). (PMID: 28962801565462110.1016/j.tins.2017.08.003)
Hong, T. T. et al. BIN1 localizes the L-type calcium channel to cardiac T-tubules. PLoS Biol. 8, e1000312 (2010). (PMID: 20169111282189410.1371/journal.pbio.1000312)
Hong, T. T. et al. BIN1 is reduced and Ca V 1.2 trafficking is impaired in human failing cardiomyocytes. Heart Rhythm 9, 812–820 (2012). (PMID: 2213847210.1016/j.hrthm.2011.11.055)
Lee, E. et al. Amphiphysin 2 (Bin1) and T-tubule biogenesis in muscle. Science 297, 1193–1196 (2002). (PMID: 1218363310.1126/science.1071362)
Hong, T. et al. Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia. Nat. Med. 20, 624–632 (2014). (PMID: 24836577404832510.1038/nm.3543)
Caldwell, J. L. et al. Dependence of cardiac transverse tubules on the BAR domain protein amphiphysin II (BIN-1). Circ. Res. 115, 986–996 (2014). (PMID: 25332206427434310.1161/CIRCRESAHA.116.303448)
De La Mata, A. et al. BIN1 induces the formation of T-tubules and adult-like Ca ²⁺ release units in developing cardiomyocytes. Stem Cells 37, 54–64 (2019). (PMID: 3035363210.1002/stem.2927)
Pant, S. et al. AMPH-1/Amphiphysin/Bin1 functions with RME-1/Ehd1 in endocytic recycling. Nat. Cell Biol. 11, 1399–1410 (2009). (PMID: 19915558278895210.1038/ncb1986)
Lambert, E. et al. The Alzheimer susceptibility gene BIN1 induces isoform-dependent neurotoxicity through early endosome defects. Acta Neuropathol. Commun. 10, 4 (2022). (PMID: 34998435874294310.1186/s40478-021-01285-5)
Tan, M. S., Yu, J. T. & Tan, L. Bridging integrator 1 (BIN1): form, function, and Alzheimer’s disease. Trends Mol. Med. 19, 594–603 (2013). (PMID: 2387143610.1016/j.molmed.2013.06.004)
Wang, H. F. et al. Bridging integrator 1 (BIN1) genotypes mediate Alzheimer’s disease risk by altering neuronal degeneration. J. Alzheimers Dis. 52, 179–190 (2016). (PMID: 2700321010.3233/JAD-150972)
Chapuis, J. et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol. Psychiatry 18, 1225–1234 (2013). (PMID: 23399914380766110.1038/mp.2013.1)
Schurmann, B. et al. A novel role for the late-onset Alzheimer’s disease (LOAD)-associated protein Bin1 in regulating postsynaptic trafficking and glutamatergic signaling. Mol. Psychiatry 25, 2000–2016 (2020). (PMID: 3096768210.1038/s41380-019-0407-3)
Perdreau-Dahl, H. et al. BIN1, myotubularin, and dynamin-2 coordinate T-tubule growth in cardiomyocytes. Circ. Res. 132, e188–e205 (2023). (PMID: 3713979010.1161/CIRCRESAHA.122.321732)
Pi, Y., Zhang, D., Kemnitz, K. R., Wang, H. & Walker, J. W. Protein kinase C and A sites on troponin I regulate myofilament Ca ²⁺ sensitivity and ATPase activity in the mouse myocardium. J. Physiol. 552, 845–857 (2003). (PMID: 12923217234344810.1113/jphysiol.2003.045260)
Kentish, J. C. et al. Phosphorylation of troponin I by protein kinase A accelerates relaxation and crossbridge cycle kinetics in mouse ventricular muscle. Circ. Res. 88, 1059–1065 (2001). (PMID: 1137527610.1161/hh1001.091640)
El-Armouche, A. et al. Decreased phosphorylation levels of cardiac myosin-binding protein-C in human and experimental heart failure. J. Mol. Cell. Cardiol. 43, 223–229 (2007). (PMID: 1756059910.1016/j.yjmcc.2007.05.003)
Kumar, M., Haghighi, K., Kranias, E. G. & Sadayappan, S. Phosphorylation of cardiac myosin-binding protein-C contributes to calcium homeostasis. J. Biol. Chem. 295, 11275–11291 (2020). (PMID: 32554466741597210.1074/jbc.RA120.013296)
Fernando, P. et al. Bin1 SRC homology 3 domain acts as a scaffold for myofiber sarcomere assembly. J. Biol. Chem. 284, 27674–27686 (2009). (PMID: 19633357278569610.1074/jbc.M109.029538)
High, K. A. & Aubourg, P. rAAV human trial experience. Methods Mol. Biol. 807, 429–457 (2011). (PMID: 2203404110.1007/978-1-61779-370-7_18)
Josephson, I. R., Guia, A., Stern, M. D. & Lakatta, E. G. Alterations in properties of L-type Ca channels in aging rat heart. J. Mol. Cell. Cardiol. 34, 297–308 (2002). (PMID: 1194502210.1006/jmcc.2001.1512)
Dibb, K. M., Rueckschloss, U., Eisner, D. A., Isenberg, G. & Trafford, A. W. Mechanisms underlying enhanced cardiac excitation contraction coupling observed in the senescent sheep myocardium. J. Mol. Cell. Cardiol. 37, 1171–1181 (2004). (PMID: 15572047)
Isenberg, G., Borschke, B. & Rueckschloss, U. Ca ²⁺ transients of cardiomyocytes from senescent mice peak late and decay slowly. Cell Calcium 34, 271–280 (2003). (PMID: 1288797410.1016/S0143-4160(03)00121-0)
Walker, K. E., Lakatta, E. G. & Houser, S. R. Age associated changes in membrane currents in rat ventricular myocytes. Cardiovasc. Res. 27, 1968–1977 (1993). (PMID: 828740510.1093/cvr/27.11.1968)
Grandy, S. A. & Howlett, S. E. Cardiac excitation-contraction coupling is altered in myocytes from aged male mice but not in cells from aged female mice. Am. J. Physiol. Heart Circ. Physiol. 291, H2362–2370, (2006). (PMID: 1673165310.1152/ajpheart.00070.2006)
Liu, S. J., Wyeth, R. P., Melchert, R. B. & Kennedy, R. H. Aging-associated changes in whole cell K ⁺ and L-type Ca ²⁺ currents in rat ventricular myocytes. Am. J. Physiol. Heart Circ. Physiol. 279, H889–900 (2000). (PMID: 1099374710.1152/ajpheart.2000.279.3.H889)
Kong, C. H. T. et al. The effects of aging on the regulation of T-tubular I Ca by caveolin in mouse ventricular myocytes. J. Gerontol. A Biol. Sci. Med Sci. 73, 711–719 (2018). (PMID: 2923699210.1093/gerona/glx242)
Rueckschloss, U., Villmow, M. & Klockner, U. NADPH oxidase-derived superoxide impairs calcium transients and contraction in aged murine ventricular myocytes. Exp. Gerontol. 45, 788–796 (2010). (PMID: 2049393910.1016/j.exger.2010.05.002)
Francis Stuart, S. D. et al. Age-related changes in cardiac electrophysiology and calcium handling in response to sympathetic nerve stimulation. J. Physiol. 596, 3977–3991 (2018). (PMID: 29938794611758310.1113/JP276396)
Janczewski, A. M., Spurgeon, H. A. & Lakatta, E. G. Action potential prolongation in cardiac myocytes of old rats is an adaptation to sustain youthful intracellular Ca ²⁺ regulation. J. Mol. Cell. Cardiol. 34, 641–648 (2002). (PMID: 1205485110.1006/jmcc.2002.2004)
White, M. et al. Age-related changes in β-adrenergic neuroeffector systems in the human heart. Circulation 90, 1225–1238 (1994). (PMID: 808793210.1161/01.CIR.90.3.1225)
Lakatta, E. G. Deficient neuroendocrine regulation of the cardiovascular-system with advancing age in healthy humans. Circulation 87, 631–636 (1993). (PMID: 842530610.1161/01.CIR.87.2.631)
Stratton, J. R. et al. Differences in cardiovascular responses to isoproterenol in relation to age and exercise training in healthy men. Circulation 86, 504–512 (1992). (PMID: 163871810.1161/01.CIR.86.2.504)
Davies, C. H., Ferrara, N. & Harding, S. E. β-adrenoceptor function changes with age of subject in myocytes from non-failing human ventricle. Cardiovasc. Res. 31, 152–156 (1996). (PMID: 8849600)
Lakatta, E. G., Gerstenblith, G., Angell, C. S., Shock, N. W. & Weisfeldt, M. L. Diminished inotropic response of aged myocardium to catecholamines. Circ. Res. 36, 262–269 (1975). (PMID: 111623610.1161/01.RES.36.2.262)
Cerbai, E. et al. β-adrenoceptor subtypes in young and old rat ventricular myocytes: a combined patch-clamp and binding study. Br. J. Pharmacol. 116, 1835–1842 (1995). (PMID: 8528568190909810.1111/j.1476-5381.1995.tb16671.x)
MacQuaide, N. et al. Ryanodine receptor cluster fragmentation and redistribution in persistent atrial fibrillation enhance calcium release. Cardiovasc. Res. 108, 387–398 (2015). (PMID: 26490742464819910.1093/cvr/cvv231)
Kolstad, T. R. et al. Ryanodine receptor dispersion disrupts Ca ²⁺ release in failing cardiac myocytes. Elife https://doi.org/10.7554/eLife.39427 (2018).
Hou, Y. et al. Nanoscale organisation of ryanodine receptors and junctophilin-2 in the failing human heart. Front. Physiol. 12, 724372 (2021). (PMID: 34690801853148010.3389/fphys.2021.724372)
Dixon, R. E., Yuan, C., Cheng, E. P., Navedo, M. F. & Santana, L. F. Ca ²⁺ signaling amplification by oligomerization of L-type Ca V 1.2 channels. Proc. Natl Acad. Sci. USA 109, 1749–1754 (2012). (PMID: 22307641327714310.1073/pnas.1116731109)
Galletta, B. J. & Cooper, J. A. Actin and endocytosis: mechanisms and phylogeny. Curr. Opin. Cell Biol. 21, 20–27 (2009). (PMID: 19186047267084910.1016/j.ceb.2009.01.006)
Hanyaloglu, A. C. & von Zastrow, M. Regulation of GPCRs by endocytic membrane trafficking and its potential implications. Annu. Rev. Pharmacol. Toxicol. 48, 537–568 (2008). (PMID: 1818410610.1146/annurev.pharmtox.48.113006.094830)
Yudowski, G. A., Puthenveedu, M. A., Henry, A. G. & von Zastrow, M. Cargo-mediated regulation of a rapid Rab4-dependent recycling pathway. Mol. Biol. Cell 20, 2774–2784 (2009). (PMID: 19369423268855610.1091/mbc.e08-08-0892)
Schulman, S. P. et al. Age-related decline in left ventricular filling at rest and exercise. Am. J. Physiol. 263, H1932–1938, (1992). (PMID: 1362335)
Fleg, J. L. & Lakatta, E. G. in Cardiovascular Disease in the Elderly 21–64 (CRC Press, 2008).
Comelli, M. et al. Rhythm dynamics of the aging heart: an experimental study using conscious, restrained mice. Am. J. Physiol. Heart Circ. Physiol. 319, H893–H905 (2020). (PMID: 32886003765465810.1152/ajpheart.00379.2020)
Piantoni, C. et al. Age-related changes in cardiac autonomic modulation and heart rate variability in mice. Front. Neurosci. 15, 617698 (2021). (PMID: 34084126816853910.3389/fnins.2021.617698)
Dai, D. F. et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 119, 2789–2797 (2009). (PMID: 19451351285875910.1161/CIRCULATIONAHA.108.822403)
Copeland, O. et al. Analysis of cardiac myosin binding protein-C phosphorylation in human heart muscle. J. Mol. Cell. Cardiol. 49, 1003–1011 (2010). (PMID: 2085045110.1016/j.yjmcc.2010.09.007)
Rosas, P. C. et al. Cardiac myosin binding protein-C phosphorylation mitigates age-related cardiac dysfunction: hope for better aging? JACC Basic Transl. Sci. 4, 817–830 (2019). (PMID: 31998850697855310.1016/j.jacbts.2019.06.003)
Wechsler-Reya, R. J., Elliott, K. J. & Prendergast, G. C. A role for the putative tumor suppressor Bin1 in muscle cell differentiation. Mol. Cell. Biol. 18, 566–575 (1998). (PMID: 941890312152410.1128/MCB.18.1.566)
Drager, N. M. et al. Bin1 directly remodels actin dynamics through its BAR domain. EMBO Rep. 18, 2051–2066 (2017). (PMID: 28893863566660510.15252/embr.201744137)
Laury-Kleintop, L. D. et al. Cardiac-specific disruption of Bin1 in mice enables a model of stress- and age-associated dilated cardiomyopathy. J. Cell Biochem. 116, 2541–2551 (2015). (PMID: 2593924510.1002/jcb.25198)
Calafate, S., Flavin, W., Verstreken, P. & Moechars, D. Loss of Bin1 promotes the propagation of tau pathology. Cell Rep. 17, 931–940 (2016). (PMID: 2776032310.1016/j.celrep.2016.09.063)
Li, J., Agvanian, S., Zhou, K., Shaw, R. M. & Hong, T. Exogenous cardiac bridging integrator 1 benefits mouse hearts with pre-existing pressure overload-induced heart failure. Front. Physiol. 11, 708 (2020). (PMID: 32670093732711310.3389/fphys.2020.00708)
National Research Council (U.S.). Committee for the update of the guide for the care and use of laboratory animals., Institute for Laboratory Animal Research (U.S.) & National Academies Press (U.S.). In Guide for the Care and Use of Laboratory Animals 8th edn (Natl Acad. Press, 2011).
Maravall, M., Mainen, Z. F., Sabatini, B. L. & Svoboda, K. Estimating intracellular calcium concentrations and buffering without wavelength ratioing. Biophys. J. 78, 2655–2667 (2000). (PMID: 10777761130085410.1016/S0006-3495(00)76809-3)
Maier, L. S. et al. Transgenic CaMKIIdeltaC overexpression uniquely alters cardiac myocyte Ca ²⁺ handling: reduced SR Ca ²⁺ load and activated SR Ca ²⁺ release. Circ. Res. 92, 904–911 (2003). (PMID: 1267681310.1161/01.RES.0000069685.20258.F1)
Du, C., MacGowan, G. A., Farkas, D. L. & Koretsky, A. P. Calibration of the calcium dissociation constant of Rhod2 in the perfused mouse heart using manganese quenching. Cell Calcium 29, 217–227 (2001). (PMID: 1124393010.1054/ceca.2000.0186)
Dixon, R. E., Vivas, O., Hannigan, K. I. & Dickson, E. J. Ground state depletion super-resolution imaging in mammalian cells. J. Vis. Exp. https://doi.org/10.3791/56239 (2017). (PMID: 10.3791/56239291557505755322)
Vigelso, A. et al. GAPDH and beta-actin protein decreases with aging, making stain-free technology a superior loading control in Western blotting of human skeletal muscle. J. Appl. Physiol. 118, 386–394 (2015). (PMID: 2542909810.1152/japplphysiol.00840.2014)
Pillai-Kastoori, L., Schutz-Geschwender, A. R. & Harford, J. A. A systematic approach to quantitative Western blot analysis. Anal. Biochem. 593, 113608 (2020). (PMID: 3200747310.1016/j.ab.2020.113608)
Pasqualin, C., Gannier, F., Malecot, C. O., Bredeloux, P. & Maupoil, V. Automatic quantitative analysis of t-tubule organization in cardiac myocytes using ImageJ. Am. J. Physiol. Cell Physiol. 308, C237–245, (2015). (PMID: 2539446910.1152/ajpcell.00259.2014)
Li, N. et al. Ablation of a Ca ²⁺ -activated K ⁺ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation. J. Physiol. 587, 1087–1100 (2009). (PMID: 19139040267377710.1113/jphysiol.2008.167718)
Thai, P. N. et al. Cardiac-specific conditional knockout of the 18-kDa mitochondrial translocator protein protects from pressure overload induced heart failure. Sci. Rep. 8, 16213 (2018). (PMID: 30385779621239710.1038/s41598-018-34451-2)

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0 (Bin1 protein, mouse)
0 (Adaptor Proteins, Signal Transducing)
0 (Tumor Suppressor Proteins)
0 (Ryanodine Receptor Calcium Release Channel)
0 (Calcium Channels, L-Type)
0 (Nuclear Proteins)
0 (RNA, Small Interfering)
0 (Nerve Tissue Proteins)

Date Created: 20240425 Date Completed: 20240425 Latest Revision: 20240527

20240528

PMC11045846

10.1038/s41467-024-47847-8

38664444