ArticleProceedings of the National Academy of Sciences of the United States of America2014
Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers.
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Who cites it
72 citing papers in PubMed, 114 citations in OpenAlex.
- Synaptic Plasticity-Intrinsic Excitability and Antidepressant Discovery.Biomedicines · 2026Review
- Heavy adolescent drinking makes the adult brain more vulnerable to ethanol by permanently altering the age-dependent interplay between alcohol, GIRK channels and activin.Molecular psychiatry · 2026Article
- Membrane-associated estrogen receptor α prevents the amyloid β-induced suppression of GIRK channel activity in hippocampal neurons from female mice.Biology of sex differences · 2025Article
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- Tolerance in Thalamic Paraventricular Nucleus Neurons Following Chronic Treatment of Animals with Morphine.eNeuro · 2025Article
- Activation of G protein gated inwardly rectifying potassium (GIRK) channels in keratinocytes mediates peripheral kappa opioid receptor-mediated antinociception.Neuropharmacology · 2025Article
- Receptor-dependent influence of R7 RGS proteins on neuronal GIRK channel signaling dynamics.Progress in neurobiology · 2024Article
- A bistable inhibitory optoGPCR for multiplexed optogenetic control of neural circuits.Nature methods · 2024Article
- Hypnotic treatment improves sleep architecture and EEG disruptions and rescues memory deficits in a mouse model of fragile X syndrome.Cell reports · 2024Article
- Molecular mechanism of GIRK2 channel gating modulated by cholesteryl hemisuccinate.Frontiers in physiology · 2024Article
- Direct modulation of G protein-gated inwardly rectifying potassium (GIRK) channels.Frontiers in physiology · 2024Review
- A muscarinic, GIRK channel-mediated inhibition of inspiratory-related XII nerve motor output emerges in early postnatal development in mice.Journal of applied physiology (Bethesda, Md. : 1985) · 2023Article
- A bistable inhibitory OptoGPCR for multiplexed optogenetic control of neural circuits.bioRxiv : the preprint server for biology · 2023Article
- Neuromedin B excites central lateral amygdala neurons and reduces cardiovascular output and fear-potentiated startle.Journal of cellular physiology · 2023Article
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- Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons.Molecular psychiatry · 2023Article
- Ionic signalling mechanisms involved in neurokinin-3 receptor-mediated augmentation of fear-potentiated startle response in the basolateral amygdala.The Journal of physiology · 2022Article
- Use of a Molecular Switch Probe to Activate or Inhibit GIRK1 Heteromers In Silico Reveals a Novel Gating Mechanism.International journal of molecular sciences · 2022Article
- Neuronal G protein-gated KAmerican journal of physiology. Cell physiology · 2022Review
- A novel small-molecule selective activator of homomeric GIRK4 channels.The Journal of biological chemistry · 2022Article
12 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
ML297 was recently identified as a potent and selective small molecule agonist of G-protein-gated inwardly rectifying K(+) (GIRK/Kir3) channels. Here, we show ML297 selectively activates recombinant neuronal GIRK channels containing the GIRK1 subunit in a manner that requires phosphatidylinositol-4,5-bisphosphate (PIP2), but is otherwise distinct from receptor-induced, G-protein-dependent channel activation. Two amino acids unique to the pore helix (F137) and second membrane-spanning (D173) domain of GIRK1 were identified as necessary and sufficient for the selective activation of GIRK channels by ML297. Further investigation into the behavioral effects of ML297 revealed that in addition to its known antiseizure efficacy, ML297 decreases anxiety-related behavior without sedative or addictive liabilities. Importantly, the anxiolytic effect of ML297 was lost in mice lacking GIRK1. Thus, activation of GIRK1-containing channels by ML297 or derivatives may represent a new approach to the treatment of seizure and/or anxiety disorders.
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Registered trials
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.