{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nREM2 is a multifunctional member of the RGK family that regulates voltage‐dependent calcium channels and cell signaling in diverse cell types. In pancreatic β‐cells, high glucose levels induce REM2 expression, which in turn potently suppresses L‐type Ca2+ channel activity and inhibits Ca2+‐triggered insulin secretion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In human pluripotent stem cells, REM2 functions as a suppressor of p53 signaling, mediating fibroblast growth factor 2 (FGF2) signals to maintain self‐renewal, promote cell cycle progression, and enhance reprogramming efficiency."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, in the context of cardiac electrophysiology, a REM2 variant was identified as a genetic modifier in long QT syndrome, where its correction reversed the enhanced L‐type Ca2+ current and prolonged action potentials in induced pluripotent stem cell–derived cardiomyocytes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the nervous system, REM2 plays a critical role in sculpting neuronal connectivity. In cultured hippocampal neurons, RNAi‐mediated knockdown of REM2 results in reduced dendritic spine density and maturity while concomitantly enhancing dendritic branching."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In addition, REM2’s subcellular distribution and its regulation of the cytoskeletal architecture underscore its role in synaptic development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Notably, REM2 directly interacts with Ca2+/calmodulin-dependent protein kinase II (CaMKII) to inhibit its activity—a mechanism essential for modulating dendritic remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOutside of excitable tissues, REM2 also influences cellular proliferation and survival. In endothelial cells, ectopic REM2 suppresses ARF expression via interactions with 14-3-3 proteins, thereby enhancing cell proliferation and implicating REM2 in angiogenic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Finally, studies in cultured hippocampal neurons suggest that while REM2 robustly inhibits voltage-gated Ca2+ channel currents when overexpressed, its knockdown does not consistently augment these currents, indicating that the role of REM2 in synaptogenesis may involve mechanisms additional to Ca2+ channel modulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Brian S Finlin, Amber L Mosley, Shawn M Crump, et al. 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