Encephalopathy-causing mutations in G beta(1) (GNB1) alter regulation of neuronal GIRK channels
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Mutations in the GNB1 gene, encoding the G beta(1) subunit of heterotrimeric G proteins, cause GNB1 Encephalopathy. Patients experience seizures, pointing to abnormal activity of ion channels or neurotransmitter receptors. We studied three G beta(1) mutations (K78R, I80N and I80T) using computational and functional approaches. In heterologous expression models, these mutations did not alter the coupling between G protein-coupled receptors to G(i/o), or the G beta gamma regulation of the neuronal voltage-gated Ca2+ channel Ca(V)2.2. However, the mutations profoundly affected the G beta gamma regulation of the G protein-gated inwardly rectifying potassium channels (GIRK, or Kir3). Changes were observed in G beta(1) protein expression levels, G beta gamma binding to cytosolic segments of GIRK subunits, and in G beta gamma function, and included gain-of-function for K78R or loss-of-function for I80T/N, which were GIRK subunit-specific. Our findings offer new insights into subunit-dependent gating of GIRKs by G beta gamma, and indicate diverse etiology of GNB1 Encephalopathy cases, bearing a potential for personalized treatment.
Original language | English |
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Article number | 103018 |
Journal | iScience |
Volume | 24 |
Issue number | 9 |
Number of pages | 29 |
ISSN | 2589-0042 |
DOIs | |
Publication status | Published - 2021 |
- G-BETA-GAMMA, ACTIVATED K+-CHANNEL, G-PROTEIN MODULATION, CALCIUM-CHANNELS, C-TERMINUS, POTASSIUM CHANNEL, STRUCTURAL BASIS, MOLECULAR-BASIS, BASAL ACTIVITY, CA2+ CHANNEL
Research areas
ID: 281705183