{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ATP2B4 encodes plasma membrane Ca²⁺‐ATPase isoform 4 (PMCA4), a key Ca²⁺ efflux pump that plays diverse roles in cellular calcium homeostasis and downstream signaling in a range of tissues. In the male reproductive tract, PMCA4 is indispensable for sperm function—it is highly expressed in testis and localized to the principal piece of the sperm tail, where it ensures proper Ca²⁺ clearance required for hyperactivated motility and male fertility. Disruption or deletion of PMCA4, whether genetically or by interfering with its delivery via exosomal pathways in the female reproductive tract, results in impaired sperm motility and infertility."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In cardiac tissue, PMCA4 functions beyond simple Ca²⁺ extrusion. It forms part of macromolecular complexes with proteins such as α1‐syntrophin and neuronal nitric oxide synthase (nNOS), thereby modulating cardiac sodium currents and β-adrenergic responsiveness; disruption of these interactions can contribute to arrhythmogenic conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, PMCA4 engages with signaling regulators including CASK, RASSF1, and calcineurin to influence transcriptional responses and Ras/Erk-driven pathways, representing a mechanism by which localized Ca²⁺ signals are translated into cellular responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": " In cardiac fibroblasts, loss of PMCA4 uncouples this regulatory network and enhances secretion of modulators (e.g., sFRP2), thereby attenuating myocyte hypertrophy under pressure overload."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In erythrocytes, ATP2B4 is responsible for the principal Ca²⁺ pumping activity, and genetic variants in this gene have been associated with altered erythrocyte calcium handling and resistance to severe falciparum malaria."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Furthermore, in bone, PMCA4 modulates Ca²⁺ oscillations that are critical for osteoclast differentiation, thereby influencing bone resorption and homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore that ATP2B4-derived PMCA4 is not only fundamental for maintaining Ca²⁺ gradients but also for orchestrating complex cellular signaling events that regulate cell motility, excitability, gene expression, and intercellular communication across multiple organ systems.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Gbolahan W Okunade, Marian L Miller, Gail J Pyne, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeted ablation of plasma membrane Ca2+-ATPase (PMCA) 1 and 4 indicates a major housekeeping function for PMCA1 and a critical role in hyperactivated sperm motility and male fertility for PMCA4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M404628200"}], "href": "https://doi.org/10.1074/jbc.M404628200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15178683"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15178683"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kai Schuh, Elizabeth J Cartwright, Eriks Jankevics, et al. 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