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 (PRRT2) as a native regulator of Nav channel slow inactivation. We show that PRRT2 facilitates the entry of Nav channels into the 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 vivo. In the mouse cortex, PRRT2 deficiency impairs the slow inactivation of Nav channels in neuronal axons, leading to reduced cortical resilience in response to hyperexcitable challenges. Together, these findings establish PRRT2 as a physiological modulator of Nav channel slow inactivation and reveal a mechanism that supports cortical resilience to pathological perturbations.