Abstract
Gap junctions (GJs), collections of multiple intercellular channels between neighboring cells, are specialized channels facilitating intercellular electrical and chemical communication. GJs are important for synchronizing coupling and coordinated contraction in the heart, and are crucial regulators of heart gene transcription, cardiac development, and protection of ischemic cardiomyocytes through second messenger communication. Identification of proteins that interact with Connexin43 (Cx43), the predominant protein in cardiac GJs, may contribute to the understanding of GJ functional regulation. Using a yeast two-hybrid system, we identified Caveolin-3 (Cav3) as a new Cx43-interacting protein. This interaction was confirmed by co-immunoprecipitation and co-localization experiments. CX43 interacts with Cav3, suggesting that Cav3 may participate in the functional regulation of GJs.
Similar content being viewed by others
References
Goldberg GS, Moreno AP, Lampe PD (2002) Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP. J Biol Chem 277:36725–36730. doi:10.1074/jbc.M109797200
Saffitz JE, Laing JG, Yamada KA (2000) Connexin expression and turnover: implications for cardiac excitability. Circ Res 86:723–728
Gutstein DE, Morley GE, Tamaddon H, Vaidya D, Schneider MD, Chen J, Chien KR, Stuhlmann H, Fishman GI (2001) Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res 88:333–339
Kaplan SR, Gard JJ, Protonotarios N, Tsatsopoulou A, Spiliopoulou C, Anastasakis A, Squarcioni CP, McKenna WJ, Thiene G, Basso C, Brousse N, Fontaine G, Saffitz JE (2004) Remodeling of myocyte gap junctions in arrhythmogenic right ventricular cardiomyopathy due to a deletion in plakoglobin (Naxos disease). Heart Rhythm 1:3–11. doi:10.1016/j.hrthm.2004.01.001
Carvajal-Huerta L (1998) Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J Am Acad Dermatol 39:418–421. doi:10.1016/S0190-9622(98)70317-2
Smith JH, Green CR, Peters NS, Rothery S, Severs NJ (1991) Altered patterns of gap junction distribution in ischemic heart disease. An immunohistochemical study of human myocardium using laser scanning confocal microscopy. Am J Pathol 139:801–821
Dupont E, Matsushita T, Kaba RA, Vozzi C, Coppen SR, Khan N, Kaprielian R, Yacoub MH, Severs NJ (2001) Altered connexin expression in human congestive heart failure. J Mol Cell Cardiol 33:359–371. doi:10.1006/jmcc.2000.1308
Peters NS, Green CR, Poole-Wilson PA, Severs NJ (1993) Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts. Circulation 88:864–875
Daleau P, Boudriau S, Michaud M, Jolicoeur C, Kingma JG Jr (2001) Preconditioning in the absence or presence of sustained ischemia modulates myocardial Cx43 protein levels and gap junction distribution. Can J Physiol Pharmacol 79:371–378. doi:10.1139/cjpp-79-5-371
Peters NS, Coromilas J, Severs NJ, Wit AL (1997) Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation 95:988–996
Matsumoto M, Hsieh TY, Zhu N, VanArsdale T, Hwang SB, Jeng KS, Gorbalenya AE, Lo SY, Ou JH, Ware CF, Lai MM (1997) Hepatitis C virus core protein interacts with the cytoplasmic tail of lymphotoxin-beta receptor. J Virol 71:1301–1309
Lin J, Friesen MT, Bocangel P, Cheung D, Rawszer K, Wigle JT (2005) Characterization of Mesenchyme Homeobox 2 (MEOX2) transcription factor binding to RING finger protein 10. Mol Cell Biochem 275:75–84. doi:10.1007/s11010-005-0823-3
Engelman JA, Zhang X, Galbiati F, Volonte D, Sotgia F, Pestell RG, Minetti C, Scherer PE, Okamoto T, Lisanti MP (1998) Molecular genetics of the caveolin gene family: implications for human cancers, diabetes, Alzheimer disease, and muscular dystrophy. Am J Hum Genet 63:1578–1587. doi:10.1086/302172
Okamoto T, Schlegel A, Scherer PE, Lisanti MP (1998) Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J Biol Chem 273:5419–5422. doi:10.1074/jbc.273.10.5419
Tang Z, Scherer PE, Okamoto T, Song K, Chu C, Kohtz DS, Nishimoto I, Lodish HF, Lisanti MP (1996) Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle. J Biol Chem 271:2255–2261. doi:10.1074/jbc.271.4.2255
Scherer PE, Okamoto T, Chun M, Nishimoto I, Lodish HF, Lisanti MP (1996) Identification, sequence, and expression of caveolin-2 defines a caveolin gene family. Proc Natl Acad Sci USA 93:131–135. doi:10.1073/pnas.93.1.131
Galbiati F, Volonte D, Chu JB, Li M, Fine SW, Fu M, Bermudez J, Pedemonte M, Weidenheim KM, Pestell RG, Minetti C, Lisanti MP (2000) Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype. Proc Natl Acad Sci USA 97:9689–9694. doi:10.1073/pnas.160249097
Feron O, Belhassen L, Kobzik L, Smith TW, Kelly RA, Michel T (1996) Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J Biol Chem 271:22810–22814. doi:10.1074/jbc.271.37.22810
Feron O, Dessy C, Opel DJ, Arstall MA, Kelly RA, Michel T (1998) Modulation of the endothelial nitric-oxide synthase-caveolin interaction in cardiac myocytes. Implications for the autonomic regulation of heart rate. J Biol Chem 273:30249–30254. doi:10.1074/jbc.273.46.30249
Venema VJ, Ju H, Zou R, Venema RC (1997) Interaction of neuronal nitric-oxide synthase with caveolin-3 in skeletal muscle. Identification of a novel caveolin scaffolding/inhibitory domain. J Biol Chem 272:28187–28190. doi:10.1074/jbc.272.45.28187
Aravamudan B, Volonte D, Ramani R, Gursoy E, Lisanti MP, London B, Galbiati F (2003) Transgenic overexpression of caveolin-3 in the heart induces a cardiomyopathic phenotype. Hum Mol Genet 12:2777–2788. doi:10.1093/hmg/ddg313
Bossuyt J, Taylor BE, James-Kracke M, Hale CC (2002) The cardiac sodium–calcium exchanger associates with caveolin-3. Ann N Y Acad Sci 976:197–204
Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, Tester DJ, Balijepalli RC, Foell JD, Li Z, Kamp TJ, Towbin JA (2006) Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 114:2104–2112. doi:10.1161/CIRCULATIONAHA.106.635268
Schubert AL, Schubert W, Spray DC, Lisanti MP (2002) Connexin family members target to lipid raft domains and interact with caveolin-1. Biochemistry 41:5754–5764. doi:10.1021/bi0121656
Saliez J, Bouzin C, Rath G, Ghisdal P, Desjardins F, Rezzani R, Rodella LF, Vriens J, Nilius B, Feron O, Balligand JL, Dessy C (2008) Role of caveolar compartmentation in endothelium-derived hyperpolarizing factor-mediated relaxation: Ca2+ signals and gap junction function are regulated by caveolin in endothelial cells. Circulation 117:1065–1074. doi:10.1161/CIRCULATIONAHA.107.731679
Acknowledgments
This work was supported by the National Natural Science Foundation of China (project number 30600254). We gratefully acknowledge the assistance of Dr. Yucai Fu, Laboratory of Cell Senescence, Shantou University Medical College, for helpful suggestions and assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Liu, L., Li, Y., Lin, J. et al. Connexin43 interacts with Caveolin-3 in the heart. Mol Biol Rep 37, 1685–1691 (2010). https://doi.org/10.1007/s11033-009-9584-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-009-9584-5