Mutations in GNB1 cause a neurological disorder characterized by general developmental delay and epileptic symptoms or seizures, intellectual disability and movement disorders. So far, tens of affected children with similar GBN1 mutations-related disorders have been described, indicating wide occurrence of the disease. GNB1 encodes the ubiquitous Gβ1 subunit of heterotrimeric G proteins, Gαβγ, which mediate the G protein-coupled receptor (GPCR) signalling. Gβ acts as an obligatory dimer with Gγ. The dominant Gβγ pair in the brain is Gβ1γ2. Major direct targets of Gβγ downstream of GPCR-initiated signalling cascades are adenylyl cyclase, PLCβ, PI3K, G protein receptor kinases, GIRK channels, voltage-gated Ca2+ channels, synaptic SNARE proteins. Most genetic epilepsies are caused by mutations in 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.
Publications:

1. Haritha P. Reddy, Daniel Yakubovich, Tal K. Raifman, Galit Tabak, Vladimir A. Tsemakhovich, Maria H. Pedersen, Boris Shalomov, Sophie Colombo, David B. Goldstein, Jonathan A. Javitch, Amal K. Bera, Nathan Dascal (2021). Encephalopathy causing mutations in Gβ1 (GNB1) alter regulation of neuronal GIRK channels. iScience. DOI:10.1016/j.isci.2021.103018
2. Divya Schidanandan, Haritha P. Reddy, Anitha Mani, Geoffrey J. Hyde, Amal K. Bera (2017). The Neuropeptide Orexin-A Inhibits the GABAA Receptor by PKC and Ca2+/CaMKII-Dependent Phosphorylation of Its β1 Subunit. Journal of Molecular Neuroscience. DOI:10.1007/s12031-017-0886-0
3. Theres Friesacher#, Haritha P. Reddy#, Harald Bernsteiner, J. Carlo Combista, Boris Shalomov, Amal K. Bera, Nathan Dascal and Anna Stary-Weinzinger. A disease mutation provides insights into gating of a K+ channel. (# equal first author). (Under revision in Communications Biology).
4. Boris Shalomov, Reem Handklo-Jamal, Haritha P. Reddy, Neta Theodor, Amal K. Bera, Nathan Dascal. A revised mechanism of action of hyperaldosteronism linked mutations in cytosolic domains of GIRK4 (KCNJ5). (Under revision in Journal of Physiology). Preprint available on BioRxiv. doi: https://doi.org/10.1101/866202
5. Sophie Colombo, Sabrina Petri, Boris Shalomov, Haritha P. Reddy, Galit Tabak, Ryan S. Dhindsa, Sahar Gelfman, Sasa Teng, Daniel Krizay, Elizabeth E. Rafikian, Amal K. Bera, Mu Yang, Michael J. Boland, Yueqing Peng, Wayne N. Frankel, Nathan Dascal, David B. Goldstein. G- protein coupled potassium channels implicated in mouse and cellular models of GNB1 encephalopathy. (Under revision in Nature Communications) Preprint available on BioRxiv. doi: https://doi.org/10.1101/697235