ArticleScience signaling2013
A computational model predicts that Gβγ acts at a cleft between channel subunits to activate GIRK1 channels.
Article in Science signaling, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 28 citations in OpenAlex.
- Live-cell quantitative monitoring reveals distinct, high-affinity Gβγ regulations of GIRK2 and GIRK1/2 channels.bioRxiv : the preprint server for biology · 2025Article
- Loss of expression and function of Gβγ by GNB1 encephalopathy-associated L95P mutation of the GβFrontiers in pharmacology · 2025Article
- Direct modulation of G protein-gated inwardly rectifying potassium (GIRK) channels.Frontiers in physiology · 2024Review
- PI(4,5)PAdvances in experimental medicine and biology · 2023Article
- From Crosstalk to Synergism: The Combined Effect of Cholesterol and PI(4,5)PAdvances in experimental medicine and biology · 2023Review
- A novel small-molecule selective activator of homomeric GIRK4 channels.The Journal of biological chemistry · 2022Article
- Encephalopathy-causing mutations in GβiScience · 2021Article
- The small molecule GAT1508 activates brain-specific GIRK1/2 channel heteromers and facilitates conditioned fear extinction in rodents.The Journal of biological chemistry · 2020Article
- A Collision Coupling Model Governs the Activation of Neuronal GIRK1/2 Channels by Muscarinic-2 Receptors.Frontiers in pharmacology · 2020Article
- On the mechanism of GIRK2 channel gating by phosphatidylinositol bisphosphate, sodium, and the Gβγ dimer.The Journal of biological chemistry · 2019Article
- Ethanol Elevates Excitability of Superior Cervical Ganglion Neurons by Inhibiting Kv7 Channels in a Cell Type-Specific and PI(4,5)PInternational journal of molecular sciences · 2019Article
- Mutual action by Gγ and Gβ for optimal activation of GIRK channels in a channel subunit-specific manner.Scientific reports · 2019Article
- The intriguing effect of ethanol and nicotine on acetylcholine-sensitive potassium current IKAch: Insight from a quantitative model.PloS one · 2019Article
- A Quantitative Model of the GIRK1/2 Channel Reveals That Its Basal and Evoked Activities Are Controlled by Unequal Stoichiometry of Gα and Gβγ.PLoS computational biology · 2015Article
- A Critical Gating Switch at a Modulatory Site in Neuronal Kir3 Channels.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Identification and Characterization of a G Protein-binding Cluster in α7 Nicotinic Acetylcholine Receptors.The Journal of biological chemistry · 2015Article
- Heterotrimeric G proteins directly regulate MMP14/membrane type-1 matrix metalloprotease: a novel mechanism for GPCR-EGFR transactivation.The Journal of biological chemistry · 2015Article
- Phosphoinositide control of membrane protein function: a frontier led by studies on ion channels.Annual review of physiology · 2015Review
- Recruitment of Gβγ controls the basal activity of G-protein coupled inwardly rectifying potassium (GIRK) channels: crucial role of distal C terminus of GIRK1.The Journal of physiology · 2014Article
- G protein-coupled receptor signaling to Kir channels in Xenopus oocytes.Current pharmaceutical biotechnology · 2014Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
The atrial G protein (heterotrimeric guanine nucleotide-binding protein)-regulated inwardly rectifying K(+) (GIRK1 and GIRK4) heterotetrameric channels underlie the acetylcholine-induced K(+) current responsible for vagal inhibition of heart rate and are activated by the G protein βγ subunits (Gβγ). We used a multistage protein-protein docking approach with data from published structures of GIRK1 and Gβγ to generate an experimentally testable interaction model of Gβγ docked onto the cytosolic domains of the GIRK1 homotetramer. The model suggested a mechanism by which Gβγ promotes the open state of a specific cytosolic gate in the channel, the G loop gate. The predicted structure showed that the Gβ subunit interacts with the channel near the site of action for ethanol and stabilizes an intersubunit cleft formed by two loops (LM and DE) of adjacent channel subunits. Using a heterologous expression system, we disrupted the predicted GIRK1- and Gβγ-interacting residues by mutation of one protein and then rescued the regulatory activity by mutating reciprocal residues in the other protein. Disulfide cross-linking of channels and Gβγ with cysteine mutations at the predicted interacting residues yielded activated channels. The mechanism of Gβγ-induced activation of GIRK4 was distinct from GIRK1 homotetramers. However, GIRK1-GIRK4 heterotetrameric channels activated by Gβγ displayed responses indicating that the GIRK1 subunit dominated the response pattern. This work demonstrated that combining computational with experimental approaches is an effective method for elucidating interactions within protein complexes that otherwise might be challenging to decipher.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.