{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC12A5, which encodes the neuron‐specific K⁺–Cl⁻ cotransporter KCC2, is pivotal in establishing the low intracellular chloride levels required for the hyperpolarizing action of GABA and glycine in mature neurons. During brain development, a marked increase in KCC2 expression drives the “GABAergic switch” by converting depolarizing, excitatory GABA responses in immature neurons into classical inhibitory signals, thereby fine‐tuning neuronal network maturation. Disruption or delayed upregulation of KCC2 has been linked to developmental disorders such as Rett syndrome and aberrant network activity in the preterm human cortex."}, {"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": "\nKCC2 function is intricately regulated by post‐translational modifications and alternative splicing that control its membrane stability, ion transport activity, and protein–protein interactions. For example, phosphorylation by protein kinase C and modulation by kinases such as WNK isoforms help stabilize KCC2 at the membrane and boost its chloride extrusion capacity. In addition, distinct N‐terminal isoforms and alternative transcripts—as well as interactions with proteins like the amyloid precursor protein—further tailor its activity and also couple chloride homeostasis to cytoskeletal dynamics."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in SLC12A5 expression and function have been implicated in a wide spectrum of neurological disorders. Genetic mutations—including compound heterozygous changes that impair KCC2’s chloride extrusion—are linked to severe epileptic syndromes such as early‐onset epileptic encephalopathies and epilepsy of infancy with migrating focal seizures. Moreover, abnormal alternative splicing and dysregulation of KCC2 have been associated with disrupted inhibitory signalling in conditions ranging from Rett syndrome and focal cortical dysplasia to schizophrenia and neuroinflammatory states like neuroHIV. Such defects affect not only synaptic inhibition but also dendritic morphology and neuronal survival, thereby impacting overall network excitability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence also indicates that SLC12A5 is aberrantly expressed beyond the nervous system and may contribute to oncogenesis. Gene amplification, mutations, and altered expression of SLC12A5 have been documented in colorectal and ovarian carcinomas, and cellular studies demonstrate that KCC2 can enhance tumor cell migration and invasion through mechanisms that are independent of its chloride transport function. These findings suggest that, in addition to its neurophysiological roles, SLC12A5 may serve as a prognostic marker and therapeutic target in certain cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies have further delineated unique transport properties of KCC2, including its constitutive ion transport activity under isotonic conditions—a property that distinguishes it from other KCC family members—and have revealed its expression in non‐neuronal cell types such as osteoblast‐like cells. These observations extend the functional repertoire of SLC12A5, suggesting roles in cell volume regulation and excitability that may be broadly relevant across different tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Claudio Rivera, Juha Voipio, Kai Kaila "}, {"type": "b", "children": [{"type": "t", "text": "Two developmental switches in GABAergic signalling: the K+-Cl- cotransporter KCC2 and carbonic anhydrase CAVII."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Physiol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1113/jphysiol.2004.077495"}], "href": "https://doi.org/10.1113/jphysiol.2004.077495"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15528236"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15528236"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sampsa Vanhatalo, J Matias Palva, Sture Andersson, et al. 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