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

iScience

Tal Keren-Raifman¹  Daniel Yakubovich²  Vladimir A. Tsemakhovich³  Nathan Dascal⁴  Jonathan A. Javitch⁵  Amal K. Bera⁶  Sophie Colombo⁷  Haritha P. Reddy⁷  Maria H. Pedersen⁷  Galit Tabak⁷  Boris Shalomov⁷  David B. Goldstein⁸ 

[1] Corresponding author;Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India;Department of Pediatrics, Schneider Children’s Medical Center, Petah Tikva, Israel;Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA;;Molecular Pharmacology and Therapeutics, Vagelos College of Physicians &Surgeons, Columbia University, New York, NY, USA;Department of Physiology and Pharmacology, School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel;;Departments of Psychiatry &

关键词: Biological sciences;    Molecular neuroscience;    Neuroscience;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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.

【 授权许可】

Unknown