PRRT2 as an auxiliary regulator of Nav channel slow inactivation
During sustained activity, voltage-gated sodium (Nav) channels enter a slow-inactivated state to limit cellular hyperexcitability. Disruption of this regulatory process has been implicated in skeletal, cardiac, and neurological disorders. While the kinetics of this process are well characterized, its endogenous modulators remain unclear. Here, we identify Proline-Rich Transmembrane Protein 2…
During persistent electrical activity, voltage-gated sodium channels traverse a sluggish deactivated phase to curb neuronal excitability. Imbalance in this regulatory mechanism has been associated with ailments ranging from skeletal to neurological origins. Although the dynamics of this process have been thoroughly explored, the intrinsic regulators remain enigmatic.
This study unveils Proline-Rich Transmembrane Protein 2 (PRRT2) as an intrinsic modulator of Nav channel sluggish inactivation. It demonstrates that PRRT2 accelerates the transition of Nav channels into the sluggish deactivated state and postpones their recuperation, a regulatory effect upheld across diverse species from zebrafish to humans.
PRRT2 establishes molecular associations with Nav channels both in vitro and in vivo. In the mouse cortex, the absence of PRRT2 undermines the sluggish inactivation of Nav channels in neuronal axons, diminishing cortical resilience to hyperexcitation. Consequently, these findings posit PRRT2 as a vital physiological regulator of Nav channel sluggish inactivation and elucidate a mechanism that fortifies cortical resilience against pathological disruptions.
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