Neuromodulation of voltage-gated sodium channels by Gβ1γ2 subunits: Implications for GNB1-linked encephalopathy

Nicholas Denomme; Samantha L Hodges; Luis Lopez-Santiago; Yukun Yuan; Julie M Ziobro; Joe Minton; Chunling Chen; Yan Chen; Jacob M Hull; James Offord; Alan V Smrcka; Lori L Isom

doi:10.1016/j.nbd.2025.106990

Neuromodulation of voltage-gated sodium channels by Gβ1γ2 subunits: Implications for GNB1-linked encephalopathy

Neurobiol Dis. 2025 Jun 5:213:106990. doi: 10.1016/j.nbd.2025.106990. Online ahead of print.

Authors

Affiliations

¹ Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
² Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
³ Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: lisom@umich.edu.

PMID: 40482731
DOI: 10.1016/j.nbd.2025.106990

Abstract

Guanine nucleotide-binding protein Gβγ subunits are ubiquitous signaling molecules that interact with numerous effector proteins in neurons, including voltage-gated sodium, calcium, and potassium channels. We show that Gβγ subunits associate with voltage-gated sodium channels (Na_vs) in mouse brain, and co-expression of a prominent Gβγ complex, Gβ1γ2, leads to functional inhibition of brain Na_v α subunit subtypes Na_v1.1 and Na_v1.6 in heterologous cells. Gβ1γ2 co-expression shows subtype-selective effects on Na_v1.1 and Na_v1.6 in the presence of Na_vβ1 subunit co-expression, and in response to prepulse voltage changes. De novo variants in GNB1, encoding the Gβ1 subunit, are linked to GNB1 encephalopathy (GNB1-E). Using cortical slice electrophysiology, we show that the Gnb1^K78R/+ mouse model of GNB1-E has reduced spontaneous GABAergic, but not glutamatergic, transmission and decreased sodium current density in dissociated parvalbumin-expressing GABAergic interneurons. This work advances our understanding of the epileptic mechanisms present in GNB1-E, including a previously unrecognized role for Na_vs.

Keywords: Developmental and epileptic encephalopathy; G-protein; GNB1; Voltage-gated sodium channel.