{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRPC5 is a versatile, non‐selective cation channel that mediates Ca²⁺ influx in response to a broad range of stimuli. Fundamental biophysical studies have shown that TRPC5 activation is initiated by G protein–coupled receptor stimulation and further modulated by intracellular Ca²⁺ elevations, specific lipid messengers such as lysophosphatidylcholine, and phosphoinositides. Its gating properties are finely tuned by redox signals, pH changes, and critical protein–protein interactions – for example through binding partners like calmodulin and SESTD1 – that couple receptor activation to downstream Ca²⁺ entry without necessarily altering its membrane density. Detailed patch‐clamp and optogenetic experiments have delineated its intrinsic properties, including modulation of open probability and sensitivity to store depletion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the nervous system, TRPC5 is expressed in both central and peripheral neurons, where it contributes to sensory transduction and neuronal plasticity. It functions as a detector of innocuous cold temperatures and is sensitive to extracellular pH fluctuations, thereby influencing neurite outgrowth, growth cone dynamics, and even aspects of innate fear behavior. Moreover, interactions with modulatory proteins – including the sigma‑1 receptor – further refine its activity in response to mechanical stimulation and other extracellular cues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDysregulation of TRPC5 has been implicated in a variety of pathological conditions. In cardiac tissue, enhanced TRPC5 expression has been observed in failing hearts, where it may contribute to maladaptive hypertrophy via Ca²⁺/calcineurin–NFAT signaling. In inflammatory diseases such as rheumatoid arthritis, extracellular reduced thioredoxin activates TRPC5 in synoviocytes, influencing secretory and inflammatory responses. In several cancers – including breast, colorectal, and glioma – elevated TRPC5 levels, and its packaging into extracellular vesicles, promote chemoresistance by triggering downstream pathways that up‐regulate multidrug efflux transporters, stimulate autophagy, and even reprogram metabolism, while also affecting cell differentiation and migration. Furthermore, altered TRPC5 function in podocytes and perhaps adipose tissue underscores its broader relevance to pathological Ca²⁺ signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdvances in pharmacology and structural biology have provided novel insights into TRPC5 modulation. The discovery of potent small‐molecule inhibitors – for example, clemizole – that block TRPC5 currents, along with recent cryo–electron microscopy studies that delineate distinct inhibitor binding sites, have revealed how such compounds stabilize the channel’s closed state. These breakthroughs support the development of selective therapeutic agents targeting TRPC5 in conditions ranging from kidney disease to neuropsychiatric disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "39", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Li-Ping He, Thamara Hewavitharana, Jonathan Soboloff, et al. 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