Encephalopathy-causing mutations in Gβ1 (GNB1) alter regulation of neuronal GIRK channels

Haritha P. Reddy, Daniel Yakubovich, Tal Keren-Raifman, Galit Tabak, Vladimir A. Tsemakhovich, Maria H. Pedersen, Boris Shalomov, Sophie Colombo, David B. Goldstein, Jonathan A. Javitch, Amal K. Bera, Nathan Dascal

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the GNB1 gene, encoding the Gβ1 subunit of heterotrimeric G proteins, cause GNB1 Encephalopathy. Patients experience seizures, pointing to abnormal activity of ion channels or neurotransmitter receptors. We studied three Gβ1 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 Gi/o, or the Gβγ regulation of the neuronal voltage-gated Ca2+ channel CaV2.2. However, the mutations profoundly affected the Gβγ regulation of the G protein-gated inwardly rectifying potassium channels (GIRK, or Kir3). Changes were observed in Gβ1 protein expression levels, Gβγ binding to cytosolic segments of GIRK subunits, and in Gβγ 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 Gβγ, and indicate diverse etiology of GNB1 Encephalopathy cases, bearing a potential for personalized treatment.

Original languageEnglish
Article number103018
JournaliScience
Volume24
Issue number9
DOIs
StatePublished - 24 Sep 2021

Keywords

  • Biological sciences
  • Molecular neuroscience
  • Neuroscience

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