{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTmem65 is a cardiac-enriched transmembrane protein that plays a critical role in organizing the intercalated disc (ICD) of cardiomyocytes. It is essential for the proper localization and stability of the gap junction protein connexin43 (Cx43), which facilitates electrical coupling between heart cells. In both mouse and zebrafish models, disruption of Tmem65 leads to internalization and accelerated degradation of Cx43, thereby compromising intercellular communication during heart development and function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies reveal that Tmem65 interacts directly with the sodium channel β1 subunit, an association important for establishing perinexal nanodomains within the ICD. This interaction not only supports the correct positioning of voltage-gated sodium channel NaV1.5 but also reinforces Cx43 localization. Reduced Tmem65 expression in mouse models impairs these interactions, leading to conduction delays and altered Ca2+ and K+ currents, though Na+ currents appear to be preserved."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these findings underscore the pivotal role of Tmem65 in maintaining ICD structural integrity and normal cardiac electrophysiology. Its disruption is associated with conduction abnormalities, suboptimal gap junction formation, and eventual cardiomyopathy marked by hypertrophy, dilation, and myocardial fibrosis. These studies highlight how Tmem65 is indispensable for preserving proper electrical signaling and mechanical stability in the heart."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Parveen Sharma, Cynthia Abbasi, Savo Lazic, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms9391"}], "href": "https://doi.org/10.1038/ncomms9391"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26403541"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26403541"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Allen C T Teng, Liyang Gu, Michelle Di Paola, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tmem65 is critical for the structure and function of the intercalated discs in mouse hearts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-022-33303-y"}], "href": "https://doi.org/10.1038/s41467-022-33303-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36257954"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36257954"}]}]}]}