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Roles of the cation–chloride cotransporters in neurological disease

Abstract

In the nervous system, the intracellular chloride concentration ([Cl]i) determines the strength and polarity of γ-aminobutyric acid (GABA)-mediated neurotransmission. [Cl]i is determined, in part, by the activities of the SLC12 cation–chloride cotransporters (CCCs). These transporters include the Na–K–2Cl cotransporter NKCC1, which mediates chloride influx, and various K–Cl cotransporters—such as KCC2 and KCC3—that extrude chloride. A precise balance between NKCC1 and KCC2 activity is necessary for inhibitory GABAergic signaling in the adult CNS, and for excitatory GABAergic signaling in the developing CNS and the adult PNS. Altered chloride homeostasis, resulting from mutation or dysfunction of NKCC1 and/or KCC2, causes neuronal hypoexcitability or hyperexcitability; such derangements have been implicated in the pathogenesis of seizures and neuropathic pain. [Cl]i is also regulated to maintain normal cell volume. Dysfunction of NKCC1 or of swelling-activated K–Cl cotransporters has been implicated in the damaging secondary effects of cerebral edema after ischemic and traumatic brain injury, as well as in swelling-related neurodegeneration. CCCs represent attractive therapeutic targets in neurological disorders the pathogenesis of which involves deranged cellular chloride homoestasis.

Key Points

  • In mammalian neurons, the strength and polarity of γ-aminobutyric acid (GABA)-mediated neurotransmission is largely determined by the intracellular chloride concentration ([Cl–]i)

  • Cation–chloride cotransporters (CCCs) have important roles in determining the [Cl–]i of both neurons and glia; the Na–K–2Cl cotransporter NKCC1 transports chloride into cells, and K–Cl cotransporters, such as KCC2 and KCC3, transport chloride out of cells

  • Altered [Cl–]i homeostasis resulting from mutation or dysfunction of NKCC1 and/or KCC2 can cause hypoexcitability or hyperexcitability of neurons; such derangements have been implicated in the pathogenesis of ischemic seizures, neonatal seizures, temporal lobe epilepsy and neuropathic pain

  • NKCC1 and the swelling-activated K–Cl cotransporters are important regulators of cell volume

  • CCCs are potential targets for novel therapeutic strategies in various neurological disorders that are characterized by deranged cellular chloride homoestasis

  • The NKCC1 inhibitor bumetanide has been shown to decrease epileptiform activity in models of neonatal seizures and temporal lobe epilepsy and to decrease cerebral edema after traumatic brain injury or stroke

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Figure 1: A developmental switch in cation–chloride cotransporter expression renders GABA hyperpolarizing during neuronal maturation.
Figure 2: Possible mechanism underlying the pathological modulation of chloride homeostasis by BDNF in seizures and neuropathic pain.
Figure 3: Regulation of cell volume by cation–chloride cotransporters.

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Acknowledgements

This article has been written in the memory of Steven C Hebert, who passed away during the final months of its preparation. He will be remembered for his keen intelligence, scientific integrity, and, above all, friendship.

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Kahle, K., Staley, K., Nahed, B. et al. Roles of the cation–chloride cotransporters in neurological disease. Nat Rev Neurol 4, 490–503 (2008). https://doi.org/10.1038/ncpneuro0883

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