A Push–Pull Mechanism Between PRRT2 and β4-subunit Differentially Regulates Membrane Exposure and Biophysical Properties of NaV1.2 Sodium Channels

Proline-rich transmembrane protein 2 (PRRT2) is a neuron-specific protein implicated in the control of neurotransmitter release and neural network stability. Accordingly, PRRT2 loss-of-function mutations associate with pleiotropic paroxysmal neurological disorders, including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine. PRRT2 is a negative modulator of the membrane exposure and biophysical properties of Na(+) channels Na(V)1.2/Na(V)1.6 predominantly expressed in brain glutamatergic neurons. Na(V) channels form complexes with β-subunits that facilitate the membrane targeting and the activation of the α-subunits. The opposite effects of PRRT2 and β-subunits on Na(V) channels raises the question of whether PRRT2 and β-subunits interact or compete for common binding sites on the α-subunit, generating Na(+) channel complexes with distinct functional properties. Using a heterologous expression system, we have observed that β-subunits and PRRT2 do not interact with each other and act as independent non-competitive modulators of Na(V)1.2 channel trafficking and biophysical properties. PRRT2 antagonizes the β4-induced increase in expression and functional activation of the transient and persistent Na(V)1.2 currents, without affecting resurgent current. The data indicate that β4-subunit and PRRT2 form a push–pull system that finely tunes the membrane expression and function of Na(V) channels and the intrinsic neuronal excitability. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-022-03112-x.