Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

Parveen Sharma, Cynthia Abbasi, Savo Lazic, Allen C.T. Teng, Dingyan Wang, Nicole Dubois, Vladimir Ignatchenko, Victoria Wong, Jun Liu, Toshiyuki Araki, Malte Tiburcy, Cameron Ackerley, Wolfram H. Zimmermann, Robert Hamilton, Yu Sun, Peter P. Liu, Gordon Keller, Igor Stagljar, Ian C. Scott, Thomas KislingerAnthony O. Gramolini

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Membrane proteins are crucial to heart function and development. Here we combine cationic silica-bead coating with shotgun proteomics to enrich for and identify plasma membrane-associated proteins from primary mouse neonatal and human fetal ventricular cardiomyocytes. We identify Tmem65 as a cardiac-enriched, intercalated disc protein that increases during development in both mouse and human hearts. Functional analysis of Tmem65 both in vitro using lentiviral shRNA-mediated knockdown in mouse cardiomyocytes and in vivo using morpholino-based knockdown in zebrafish show marked alterations in gap junction function and cardiac morphology. Molecular analyses suggest that Tmem65 interaction with connexin 43 (Cx43) is required for correct localization of Cx43 to the intercalated disc, since Tmem65 deletion results in marked internalization of Cx43, a shorter half-life through increased degradation, and loss of Cx43 function. Our data demonstrate that the membrane protein Tmem65 is an intercalated disc protein that interacts with and functionally regulates ventricular Cx43.

Original languageEnglish
Article number8391
JournalNature Communications
StatePublished - 25 Sep 2015
Externally publishedYes


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