{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRPC6 is a diacylglycerol‐activated, non–voltage‐gated cation channel that plays a central role in mediating receptor‐operated Ca²⁺ influx. At the molecular level, TRPC6 assembles as a homotetramer or in heteromeric complexes within the TRPC3/6/7 subfamily, and its activity is finely tuned by several mechanisms. Post–translational modifications such as glycosylation help set its basal versus receptor‐regulated state, while receptor stimulation not only generates diacylglycerol but also promotes exocytotic insertion of the channel into the plasma membrane. In addition, lipid regulators—most notably phosphatidylinositol 3,4,5–trisphosphate that directly binds to TRPC6 and alters its interaction with calmodulin—and interactions with Orai proteins further modulate its sensitivity to store depletion. Subtle cooperative influences from actin regulatory proteins (e.g. Ena/VASP, known to organize the cortical cytoskeleton) may also mold the local signaling environment in which TRPC6 functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn diverse excitable and non‐excitable cell types, TRPC6‐mediated Ca²⁺ entry establishes critical signals for both normal physiology and disease. In the kidney, for example, TRPC6 is highly expressed in podocytes where gain‐of–function mutations enhance Ca²⁺ influx and activate downstream calcineurin–NFAT signaling, ultimately contributing to focal and segmental glomerulosclerosis. Similarly, in vascular smooth muscle and endothelial cells, TRPC6 underlies receptor– and mechanically–induced Ca²⁺ influx that drives cell contraction, proliferation, and even the regulation of specialized processes such as leukocyte transendothelial migration. Additional contributions in mesangial and airway smooth muscle cells, as well as its coupling with exchangers and other membrane proteins like BK(Ca) channels, underscore the channel’s multifaceted role in tuning vascular tone and in the progression of pulmonary and vascular pathologies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical roles in calcium homeostasis and contractility, TRPC6‐mediated Ca²⁺ signals have been increasingly implicated in pathologic conditions spanning the nervous system, cancer, and beyond. In transformed cells, aberrant TRPC6 activity promotes proliferative pathways in gastric cancer, glioma, and glioblastoma, and in hepatocellular carcinoma TRPC6 contributes to multidrug resistance via downstream STAT3 activation. Moreover, in neuronal models, TRPC6 insufficiency or haploinsufficiency has been linked to altered neuronal development in autism spectrum disorders. TRPC6 also participates in non–canonical roles; for example, by mediating Ca²⁺ leak in erythrocytes that leads to programmed cell death and by triggering keratinocyte differentiation. Collectively, these studies reinforce that TRPC6 is a versatile channel whose dysregulation—in combination with altered lipid modulation, cytoskeletal interactions, and cross–talk with other Ca²⁺–handling proteins—has broad pathophysiological consequences."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Keow Lin Goh, Li Cai, Constance L Cepko, et al. 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