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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| Format: | Article |
| Language: | English |
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Elsevier
2025-09-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002062 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Nicholas Denomme |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-796bca3e4fc14466bddc3c84bdd61c9f |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-796bca3e4fc14466bddc3c84bdd61c9f2025-08-20T03:32:23ZengElsevierNeurobiology of Disease1095-953X2025-09-0121310699010.1016/j.nbd.2025.106990Neuromodulation of voltage-gated sodium channels by Gβ1γ2 subunits: Implications for GNB1-linked encephalopathyNicholas Denomme0Samantha L. Hodges1Luis Lopez-Santiago2Yukun Yuan3Julie M. Ziobro4Joe Minton5Chunling Chen6Yan Chen7Jacob M. Hull8James Offord9Alan V. Smrcka10Lori L. Isom11Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USADepartment of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S0969996125002062Voltage-gated sodium channelG-proteinGNB1Developmental and epileptic encephalopathy |
| spellingShingle | 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 Neuromodulation of voltage-gated sodium channels by Gβ1γ2 subunits: Implications for GNB1-linked encephalopathy Neurobiology of Disease Voltage-gated sodium channel G-protein GNB1 Developmental and epileptic encephalopathy |
| title | Neuromodulation of voltage-gated sodium channels by Gβ1γ2 subunits: Implications for GNB1-linked encephalopathy |
| title_full | Neuromodulation of voltage-gated sodium channels by Gβ1γ2 subunits: Implications for GNB1-linked encephalopathy |
| title_fullStr | Neuromodulation of voltage-gated sodium channels by Gβ1γ2 subunits: Implications for GNB1-linked encephalopathy |
| title_full_unstemmed | Neuromodulation of voltage-gated sodium channels by Gβ1γ2 subunits: Implications for GNB1-linked encephalopathy |
| title_short | Neuromodulation of voltage-gated sodium channels by Gβ1γ2 subunits: Implications for GNB1-linked encephalopathy |
| title_sort | neuromodulation of voltage gated sodium channels by gβ1γ2 subunits implications for gnb1 linked encephalopathy |
| topic | Voltage-gated sodium channel G-protein GNB1 Developmental and epileptic encephalopathy |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125002062 |
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