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      WNK1/HSN2 kinase inhibition ameliorates neuropathic pain by reducing maladaptive KCC2 inhibitory phosphorylation and restoring GABA inhibition

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          Abstract

          WNK1/HSN2 kinase, mutated in a Mendelian form of congenital pain insensitivity, contributes to a maladaptive decrease in KCC2 cotransporter activity and a loss of GABA inhibition in the spared nerve injury (SNI) model of neuropathic pain by increasing KCC2 inhibitory phosphorylation at Thr906/Thr1007. Antagonizing WNK1/HSN2 signaling reduces SNI-induced cold allodynia and mechanical hyperalgesia, decreases up-regulated KCC2 Thr906/Thr1007 phosphorylation, and normalizes pathological GABA depolarizations of injured spinal cord lamina II neurons. These data collectively provide novel mechanistic insight into, and a compelling therapeutic target for, neuropathic pain after nerve injury.

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          Harnessing homologous recombination in vitro to generate recombinant DNA via SLIC.

          Mamie Z Li, Stephen J. Elledge (2007)
          We describe a new cloning method, sequence and ligation-independent cloning (SLIC), which allows the assembly of multiple DNA fragments in a single reaction using in vitro homologous recombination and single-strand annealing. SLIC mimics in vivo homologous recombination by relying on exonuclease-generated ssDNA overhangs in insert and vector fragments, and the assembly of these fragments by recombination in vitro. SLIC inserts can also be prepared by incomplete PCR (iPCR) or mixed PCR. SLIC allows efficient and reproducible assembly of recombinant DNA with as many as 5 and 10 fragments simultaneously. SLIC circumvents the sequence requirements of traditional methods and functions much more efficiently at very low DNA concentrations when combined with RecA to catalyze homologous recombination. This flexibility allows much greater versatility in the generation of recombinant DNA for the purposes of synthetic biology.
          Article 0 comments Cited 338 times – based on 0 reviews     Review now
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            Human hypertension caused by mutations in WNK kinases.

            F. Wilson, S Disse-Nicodème, K A Choate … (2001)
            Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.
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              Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain.

              Jeffrey A M Coull, Dominic Boudreau, Karine Bachand … (2003)
              Modern pain-control theory predicts that a loss of inhibition (disinhibition) in the dorsal horn of the spinal cord is a crucial substrate for chronic pain syndromes. However, the nature of the mechanisms that underlie such disinhibition has remained controversial. Here we present evidence for a novel mechanism of disinhibition following peripheral nerve injury. It involves a trans-synaptic reduction in the expression of the potassium-chloride exporter KCC2, and the consequent disruption of anion homeostasis in neurons of lamina I of the superficial dorsal horn, one of the main spinal nociceptive output pathways. In our experiments, the resulting shift in the transmembrane anion gradient caused normally inhibitory anionic synaptic currents to be excitatory, substantially driving up the net excitability of lamina I neurons. Local blockade or knock-down of the spinal KCC2 exporter in intact rats markedly reduced the nociceptive threshold, confirming that the reported disruption of anion homeostasis in lamina I neurons was sufficient to cause neuropathic pain.
              Article 0 comments Cited 267 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101465400
                Journal ID (pubmed-jr-id): 34171
                Journal ID (nlm-ta): Sci Signal
                Journal ID (iso-abbrev): Sci Signal
                Title: Science signaling
                ISSN (Print): 1945-0877
                ISSN (Electronic): 1937-9145
                Publication date Nihms-submitted: 8 April 2017
                Publication date (Electronic): 29 March 2016
                Publication date Collection: 29 March 2016
                Publication date PMC-release: 09 December 2017
                Volume: 9
                Issue: 421
                Page: ra32
                Affiliations
                [1 ]Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston (MA) 02115, USA
                [2 ]Department of Neurosurgery, Boston Children’s Hospital, Boston (MA), 02124 USA
                [3 ]Montreal Neurological Institute and Hospital, McGill University, Montréal (QC), H3A 2B4, Canada
                [4 ]Department of Neurology and Neurosurgery, McGill University, Montréal (QC), Canada
                [5 ]F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston (MA), 02115, USA
                [6 ]MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland
                [7 ]Department of Psychology and Centre for Research on Pain, McGill University, Montréal (QC), H3A 0G1, Canada
                [8 ]Institut des Neurosciences Cellulaires et Integratives, UPR 3212 Centre National de la Recherche Scientifique, Strasbourg, France; Universite de Strasbourg, 5 rue Blaise Pascal, F-67084, Strasbourg, France
                Author notes
                [* ]To whom correspondence should be addressed: Guy A. Rouleau M.D., Ph.D., F.R.C.P.C., Phone: +1-514-398-2690, Fax: +1-514-398-8248, guy.rouleau@ 123456mcgill.ca ; Kristopher T. Kahle M.D., Ph.D., Phone: +1-203-737-2096, Fax: +1-203-785-2044, kristopher.kahle@ 123456yale.edu
                [†]

                These authors contributed equally to this work.

                [#]

                Current affiliation: Departments of Neurosurgery, Pediatrics, and Cellular and Molecular Physiology, Yale School of Medicine, New Haven (CT) 06511 USA

                Article
                Accession ID: PMC5723157 Pmcid ID: PMC5723157 Pmc-uid ID: 5723157 Manuscript ID: nihpa862166
                DOI: 10.1126/scisignal.aad0163
                PMC ID: 5723157
                PubMed ID: 27025876
                SO-VID: be71eac0-e024-473d-83eb-cde685cc2271
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