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Papers of the Week

Papers: 26 Nov 2022 - 2 Dec 2022

Animal Studies

2022 Nov 28

Mol Neurobiol

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


Valente P, Marte A, Franchi F, Sterlini B, Casagrande S, Corradi A, Baldelli P, Benfenati F
Mol Neurobiol. 2022 Nov 28.
PMID: 36441479.


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 Na1.2/Na1.6 predominantly expressed in brain glutamatergic neurons. Na 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 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 Na1.2 channel trafficking and biophysical properties. PRRT2 antagonizes the β4-induced increase in expression and functional activation of the transient and persistent Na1.2 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 channels and the intrinsic neuronal excitability.