Neuromodulation of voltage-gated sodium channels by Gβ1γ2 subunits: Implications for GNB1-linked encephalopathy
Summary: 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 (Navs) in mous...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-09-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002062 |
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| Summary: | Summary: 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 (Navs) in mouse brain, and co-expression of a prominent Gβγ complex, Gβ1γ2, leads to functional inhibition of brain Nav α subunit subtypes Nav1.1 and Nav1.6 in heterologous cells. Gβ1γ2 co-expression shows subtype-selective effects on Nav1.1 and Nav1.6 in the presence of Navβ1 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 Gnb1K78R/+ 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 Navs. |
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| ISSN: | 1095-953X |