Upregulation of the persistent sodium current in motoneurons contributes to the development of spasticity after spinal cord injury (SCI). We investigated the mechanisms that regulate INaP and observed elevated expression of voltage-gated sodium (Nav) 1.6 channels in spinal lumbar motoneurons of adult rats with Spinal cord injury. Furthermore, immunoblots revealed a proteolysis of Nav channels, and biochemical assays identified calpain as the main proteolytic factor. Calpain-dependent cleavage of Nav channels was associated with an upregulation of INaP in motoneurons. Similarly, the calpain-dependent cleavage of Nav1.6 channels expressed in human embryonic kidney (HEK) 293 cells caused the upregulation of INaP. The pharmacological inhibition of calpain activity by MDL28170 (Calpain inhibitor) reduced the cleavage of Nav channels, INaP in motoneurons and spasticity in rats with SCI. Similarly, the blockade of INaP 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 INaP and spasticity.
What has this got to do with multiple sclerosis you say?
There are nine voltage dependent sodium channels (Nav) and Nav 1.6 is one of the important ones.
They are upregulated in demyelinated nerves and so is one of the targets for sodium channel blockers, which can be neuroprotective because they stop nerve energy depletion caused by the energy required to get rid of sodium from inside the cell.
In this study they find Sodium channels are increased in motor nerves, which may be part of the pathology or as a consequence of firing more often a occurs in spasticity. The sodium channels can be cleaved and deformation of the channel can lead to elevated calcium current and persistent sodium currents leading to spasticity. In this study they find that calpain activation causes the cleavage of the sodium channel leading to spasticity. So this can be inhibited by calpain inhibitors and riluzole can block this sodium curent too…So this is the Nature Medicine….However some medicine I wonder.
In this study the authors record spasms off a flexor muscle. What’s the surprise in this?
Glutamate receptor stimulation increases calcium activation and so together they block influx of sodium and calcium which is going to stop depolarisation (loss of nerve membrane charge which occurs when a nerve fires. Sodium channels open allowing sodium to enter the cells causing the inside of the nerve to become more positively charged compared to the outside = depolarisation.