Cleavage of Na+ channels by calpain increases persistent Na+ current and promotes spasticity after spinal cord injury | Zendy

Cécile Brocard | Zendy; Vanessa Plantier | Zendy; Pascale Boulenguez | Zendy; Sylvie Liabeuf | Zendy; Mouloud Bouhadfane | Zendy; Annelise Viallat-Lieutaud | Zendy; Laurent Vinay | Zendy; Frédéric Brocard | Zendy

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Cleavage of Na+ channels by calpain increases persistent Na+ current and promotes spasticity after spinal cord injury

Author(s) -

Cécile Brocard,

Vanessa Plantier,

Pascale Boulenguez,

Sylvie Liabeuf,

Mouloud Bouhadfane,

Annelise Viallat-Lieutaud,

Laurent Vinay,

Frédéric Brocard

Publication year - 2016

Publication title -

nature medicine

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 19.536

H-Index - 547

eISSN - 1546-170X

pISSN - 1078-8956

DOI - 10.1038/nm.4061

Subject(s) - calpain , downregulation and upregulation , spinal cord , spasticity , sodium channel , spinal cord injury , neuroscience , chemistry , microbiology and biotechnology , medicine , biology , anesthesia , sodium , biochemistry , gene , enzyme , organic chemistry

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.

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