RGD Reference Report - Mechanism underlying selective regulation of G protein-gated inwardly rectifying potassium channels by the psychostimulant-sensitive sorting nexin 27.

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Mechanism underlying selective regulation of G protein-gated inwardly rectifying potassium channels by the psychostimulant-sensitive sorting nexin 27.
Authors:	Balana, B Maslennikov, I Kwiatkowski, W Stern, KM Bahima, L Choe, S Slesinger, PA
Citation:	Balana B, etal., Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5831-6. doi: 10.1073/pnas.1018645108. Epub 2011 Mar 21.
RGD ID:	8554349
Pubmed:	PMID:21422294 (View Abstract at PubMed)
PMCID:	PMC3078414 (View Article at PubMed Central)
DOI:	DOI:10.1073/pnas.1018645108 (Journal Full-text)
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-Phi, where X is any residue and Phi 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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Biological Process

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Snx27	Rat	negative regulation of inward rectifier potassium channel activity		IDA			RGD

Cellular Component

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Snx27	Rat	early endosome	located_in	IDA		PMID:21422294	UniProt

Molecular Function

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Kcnj9	Rat	PDZ domain binding	enables	IPI	UniProtKB:Q8K4V4	PMID:21422294	UniProt
Kcnj9	Rat	PDZ domain binding		IPI	Snx27 (Rattus norvegicus)		RGD
Snx27	Rat	protein binding	enables	IPI	UniProtKB:Q63511	PMID:21422294	UniProt
Snx27	Rat	protein binding		IPI	Kcnj9 (Rattus norvegicus)		RGD

Objects Annotated

Genes (Rattus norvegicus)

Kcnj9 (potassium inwardly-rectifying channel, subfamily J, member 9)

Snx27 (sorting nexin 27)

Additional Information

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InterViewer (Protein-Protein Interactions)	GViewer (Genome Viewer)	Variant Visualizer (Damaging Variants)

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Mechanism underlying selective regulation of G protein-gated inwardly rectifying potassium channels by the psychostimulant-sensitive sorting nexin 27.