PRRT2 as an auxiliary regulator of Nav channel slow inactivation

During sustained activity, voltage-gated sodium (Nav) channels enter a slow inactivation 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 (PRRT2) as a native regulator of Nav channel slow inactivation. We show that PRRT2 facilitates the entry of Nav channels into slow-inactivated state and delays their recovery, a regulatory effect conserved from zebrafish to humans. PRRT2 forms molecular complexes with Nav channels both in vitro and in vi