title: Cleavage of Na(+) channels by calpain increases persistent Na(+) current and promotes spasticity after spinal cord injury.
abstract: Upregulation of the persistent sodium current (I(NaP)) in motoneurons contributes to the development of spasticity after spinal cord injury (SCI). We investigated the mechanisms that regulate I(NaP) and observed elevated expression of voltage-gated sodium (Nav) 1.6 channels in spinal lumbar motoneurons of adult rats with SCI. Furthermore, immunoblots revealed a proteolysis of Nav channels, and biochemical assays identified calpain as the main proteolytic factor. Calpain-dependent cleavage of Nav channels after neonatal SCI was associated with an upregulation of I(NaP) in motoneurons. Similarly, the calpain-dependent cleavage of Nav1.6 channels expressed in human embryonic kidney (HEK) 293 cells caused the upregulation of I(NaP). The pharmacological inhibition of calpain activity by MDL28170 reduced the cleavage of Nav channels, I(NaP) in motoneurons and spasticity in rats with SCI. Similarly, the blockade of I(NaP) by riluzole alleviated spasticity. This study demonstrates that Nav channel expression in lumbar motoneurons is altered after SCI, and it shows a tight relationship between the calpain-dependent proteolysis of Nav1.6 channels, the upregulation of I(NaP) and spasticity.
authors.affiliation: Team P3M, Institut de Neurosciences de la Timone, UMR7289, Aix-Marseille Université and Centre National de la Recherche Scientifique (CNRS), Marseille, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Brocard
authors.affiliation: Team P3M, Institut de Neurosciences de la Timone, UMR7289, Aix-Marseille Université and Centre National de la Recherche Scientifique (CNRS), Marseille, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Plantier
authors.affiliation: Team P3M, Institut de Neurosciences de la Timone, UMR7289, Aix-Marseille Université and Centre National de la Recherche Scientifique (CNRS), Marseille, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Boulenguez
authors.affiliation: Team P3M, Institut de Neurosciences de la Timone, UMR7289, Aix-Marseille Université and Centre National de la Recherche Scientifique (CNRS), Marseille, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Liabeuf
authors.affiliation: Team P3M, Institut de Neurosciences de la Timone, UMR7289, Aix-Marseille Université and Centre National de la Recherche Scientifique (CNRS), Marseille, France.
authors.forename: Mouloud
authors.initials: M
authors.lastname: Bouhadfane
authors.affiliation: Team P3M, Institut de Neurosciences de la Timone, UMR7289, Aix-Marseille Université and Centre National de la Recherche Scientifique (CNRS), Marseille, France.
authors.forename: Annelise
authors.initials: A
authors.lastname: Viallat-Lieutaud
authors.affiliation: Team P3M, Institut de Neurosciences de la Timone, UMR7289, Aix-Marseille Université and Centre National de la Recherche Scientifique (CNRS), Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vinay
authors.affiliation: Team P3M, Institut de Neurosciences de la Timone, UMR7289, Aix-Marseille Université and Centre National de la Recherche Scientifique (CNRS), Marseille, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Brocard
mesh_terms: D000818:Animals; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D004151:Dipeptides / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000096:biosynthesis / Q000378:metabolism; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000096:biosynthesis* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D019782:Riluzole / Q000008:administration & dosage; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013119:Spinal Cord Injuries / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D004151:Dipeptides; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; C568250:Scn1a protein, rat; C507811:Scn8a protein, rat; D019782:Riluzole; D002154:Calpain; C058076:calpain inhibitor III