Editors' ChoiceNeuroscience

New connections: Setting the GABA response

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Science Signaling  29 Mar 2016:
Vol. 9, Issue 421, pp. ec76
DOI: 10.1126/scisignal.aaf7583

The neurotransmitter GABA (γ-aminobutyric acid) signals through both metabotropic receptors and ionotropic receptors. The ionotropic receptors function as a Cl channel. In 2015, Friedel et al. showed that a kinase pathway involving the kinases WNK and SPAK, and the SPAK-related kinase OSR, inhibits the activity of KCC2, a K+, Cl cotransporter, in immature hippocampal neurons. The result of inhibiting KCC2 is an increased concentration of Cl inside the neurons. Consequently, when GABA activates its ionotropic receptor, Cl leaves the neurons (enhancing synaptic responsiveness), rather than enters the neurons (reducing synaptic responsiveness). In this week’s issue, Kahle et al. report that ablating a specific splice variant of WNK1 (WNK1/HSN2) protects mice from the development of neuropathic pain resulting from severed nerve injury. The mechanism was restoration of GABA-mediated inhibition in the spinal cord neurons by reducing intracellular Cl through alleviation of WNK-mediated inhibition of KCC2. The ability to therapeutically target this WNK-KCC2 pathway may be beneficial in treating not only neuropathic pain, which is characterized by GABAergic disinhibition (inappropriate GABA-mediated enhancement of synaptic activity), but also neurological and neuropsychiatric conditions associated with GABAergic disinhibition, such as autism, febrile seizures, and epilepsy.

P. Friedel, K. T. Kahle, J. Zhang, N. Hertz, L. I. Pisella, E. Buhler, F. Schaller, J. Duan, A. R. Khanna, P. N. Bishop, K. M. Shokat, I. Medina, WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons. Sci. Signal. 8, ra65 (2015). [Abstract]

K. T. Kahle, J.-F. Schmouth, V. Lavastre, A. Latremoliere, J. Zhang, N. Andrews, T. Omura, J. Laganière, D. Rochefort, P. Hince, G. Castonguay, R. Gaudet, J. C. S. Mapplebeck, S. G. Sotocinal, J. Duan, C. Ward, A. R. Khanna, J. S. Mogil, P. A. Dion, C. J. Woolf, P. Inquimbert, G. A. Rouleau, Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition. Sci. Signal. 9, ra32 (2016). [Abstract]

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