Encephalopathy-causing mutations in G beta(1) (GNB1) alter regulation of neuronal GIRK channels

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Encephalopathy-causing mutations in G beta(1) (GNB1) alter regulation of neuronal GIRK channels. / Reddy, Haritha P.; Yakubovich, Daniel; Keren-Raifman, Tal; Tabak, Galit; Tsemakhovich, Vladimir A.; Pedersen, Maria H.; Shalomov, Boris; Colombo, Sophie; Goldstein, David B.; Javitch, Jonathan A.; Bera, Amal K.; Dascal, Nathan.

In: iScience, Vol. 24, No. 9, 103018, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Reddy, HP, Yakubovich, D, Keren-Raifman, T, Tabak, G, Tsemakhovich, VA, Pedersen, MH, Shalomov, B, Colombo, S, Goldstein, DB, Javitch, JA, Bera, AK & Dascal, N 2021, 'Encephalopathy-causing mutations in G beta(1) (GNB1) alter regulation of neuronal GIRK channels', iScience, vol. 24, no. 9, 103018. https://doi.org/10.1016/j.isci.2021.103018

APA

Reddy, H. P., Yakubovich, D., Keren-Raifman, T., Tabak, G., Tsemakhovich, V. A., Pedersen, M. H., Shalomov, B., Colombo, S., Goldstein, D. B., Javitch, J. A., Bera, A. K., & Dascal, N. (2021). Encephalopathy-causing mutations in G beta(1) (GNB1) alter regulation of neuronal GIRK channels. iScience, 24(9), [103018]. https://doi.org/10.1016/j.isci.2021.103018

Vancouver

Reddy HP, Yakubovich D, Keren-Raifman T, Tabak G, Tsemakhovich VA, Pedersen MH et al. Encephalopathy-causing mutations in G beta(1) (GNB1) alter regulation of neuronal GIRK channels. iScience. 2021;24(9). 103018. https://doi.org/10.1016/j.isci.2021.103018

Author

Reddy, Haritha P. ; Yakubovich, Daniel ; Keren-Raifman, Tal ; Tabak, Galit ; Tsemakhovich, Vladimir A. ; Pedersen, Maria H. ; Shalomov, Boris ; Colombo, Sophie ; Goldstein, David B. ; Javitch, Jonathan A. ; Bera, Amal K. ; Dascal, Nathan. / Encephalopathy-causing mutations in G beta(1) (GNB1) alter regulation of neuronal GIRK channels. In: iScience. 2021 ; Vol. 24, No. 9.

Bibtex

@article{88cb850e2c254789aa5115c75a574b20,
title = "Encephalopathy-causing mutations in G beta(1) (GNB1) alter regulation of neuronal GIRK channels",
abstract = "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.",
keywords = "G-BETA-GAMMA, ACTIVATED K+-CHANNEL, G-PROTEIN MODULATION, CALCIUM-CHANNELS, C-TERMINUS, POTASSIUM CHANNEL, STRUCTURAL BASIS, MOLECULAR-BASIS, BASAL ACTIVITY, CA2+ CHANNEL",
author = "Reddy, {Haritha P.} and Daniel Yakubovich and Tal Keren-Raifman and Galit Tabak and Tsemakhovich, {Vladimir A.} and Pedersen, {Maria H.} and Boris Shalomov and Sophie Colombo and Goldstein, {David B.} and Javitch, {Jonathan A.} and Bera, {Amal K.} and Nathan Dascal",
year = "2021",
doi = "10.1016/j.isci.2021.103018",
language = "English",
volume = "24",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier",
number = "9",

}

RIS

TY - JOUR

T1 - Encephalopathy-causing mutations in G beta(1) (GNB1) alter regulation of neuronal GIRK channels

AU - Reddy, Haritha P.

AU - Yakubovich, Daniel

AU - Keren-Raifman, Tal

AU - Tabak, Galit

AU - Tsemakhovich, Vladimir A.

AU - Pedersen, Maria H.

AU - Shalomov, Boris

AU - Colombo, Sophie

AU - Goldstein, David B.

AU - Javitch, Jonathan A.

AU - Bera, Amal K.

AU - Dascal, Nathan

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - G-BETA-GAMMA

KW - ACTIVATED K+-CHANNEL

KW - G-PROTEIN MODULATION

KW - CALCIUM-CHANNELS

KW - C-TERMINUS

KW - POTASSIUM CHANNEL

KW - STRUCTURAL BASIS

KW - MOLECULAR-BASIS

KW - BASAL ACTIVITY

KW - CA2+ CHANNEL

U2 - 10.1016/j.isci.2021.103018

DO - 10.1016/j.isci.2021.103018

M3 - Journal article

C2 - 34522861

VL - 24

JO - iScience

JF - iScience

SN - 2589-0042

IS - 9

M1 - 103018

ER -

ID: 281705183