Mechanism underlying selective regulation of G protein-gated inwardly rectifying potassium channels by the psychostimulant-sensitive sorting nexin 27
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G protein-gated inwardly rectifying potassium (GIRK) channels are important gatekeepers of neuronal excitability. The surface expression of neuronal GIRK channels is regulated by the psychostimulant-sensitive sorting nexin 27 (SNX27) protein through a class I (-X-Ser/Thr-X-Φ, where X is any residue and Φ is a hydrophobic amino acid) PDZ-binding interaction. The G protein-insensitive inward rectifier channel (IRK1) contains the same class I PDZ-binding motif but associates with a different synaptic PDZ protein, postsynaptic density protein 95 (PSD95). The mechanism by which SNX27 and PSD95 discriminate these channels was previously unclear. Using high-resolution structures coupled with biochemical and functional analyses, we identified key amino acids upstream of the channel's canonical PDZ-binding motif that associate electrostatically with a unique structural pocket in the SNX27-PDZ domain. Changing specific charged residues in the channel's carboxyl terminus or in the PDZ domain converts the selective association and functional regulation by SNX27. Elucidation of this unique interaction site between ion channels and PDZ-containing proteins could provide a therapeutic target for treating brain diseases.
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Several types of K+ channels function as general gatekeepers of neuronal excitability in numerous experimental systems.
“there is increasing evidence that several types of K+ channels function as general gatekeepers of neuronal excitability in numerous experimental systems79, 80”
From Neurobiology of resilience (2012) · cites this paper as [80]
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Self-citation
- Authors
- Balana, B., Maslennikov, I., Kwiatkowski, W., Stern, K. M., Bahima, L., Choe, S., & Slesinger, P. A.
- Affiliations
- Salk Institute for Biological Studies (US)
- Clayton Foundation (CH)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-03-21
- Volume
- 108
- Issue
- 14
- Pages
- 5831-5836
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3078414
- OpenAlex
- W2087336695
- Cited by
- 89
- References
- 41
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 7 · 2021: 7 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 7 · 2016: 12 · 2015: 6 · 2014: 11 · 2013: 10 · 2012: 3
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (R01DA019022, DA019022)
- National Institute of General Medical Sciences (GM521223)
- National Institute of Neurological Disorders and Stroke (R01NS037682, NS 37682)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- G protein-coupled inwardly rectifying potassium channels, GIRK channels, SNX27, PDZ-binding motif, PSD-95, Kir2.1, neuronal excitability, electrostatic interactions, psychostimulants
- MeSH terms
- Disks Large Homolog 4 Protein, Animals, Chlorocebus aethiops, Crystallization, Electrophysiology, Hippocampus, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Membrane Proteins, Models, Molecular, Neurons, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Microscopy, Confocal, COS Cells, Amino Acid Motifs, Intracellular Signaling Peptides and Proteins, Rats, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Sorting Nexins
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