*Result*: A hierarchy of PDZ domain scaffolding proteins clusters the Kv1 K + channel protein complex at the axon initial segment.
Title:
A hierarchy of PDZ domain scaffolding proteins clusters the Kv1 K + channel protein complex at the axon initial segment.
Authors:
Zhang W; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA., Palfini VL; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA., Wu Y; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA., Ding X; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA., Melton AJ; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA., Gao Y; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA., Ogawa Y; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA., Rasband MN; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
Source:
Science advances [Sci Adv] 2025 May 23; Vol. 11 (21), pp. eadv1281. Date of Electronic Publication: 2025 May 23.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE
Imprint Name(s):
Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-
MeSH Terms:
PDZ Domains* , Shaker Superfamily of Potassium Channels*/metabolism , Shaker Superfamily of Potassium Channels*/genetics , Axon Initial Segment*/metabolism , Axons*/metabolism, Animals ; Protein Binding ; Humans ; Rats ; Membrane Proteins/metabolism ; Membrane Proteins/genetics ; HEK293 Cells ; Kv Channel-Interacting Proteins/metabolism
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Nat Commun. 2023 Dec 11;14(1):8201. (PMID: 38081810)
Sci Adv. 2023 Jul 14;9(28):eadf7084. (PMID: 37450597)
Nat Rev Neurosci. 2010 Aug;11(8):552-62. (PMID: 20631711)
BMC Biol. 2011 Sep 29;9:66. (PMID: 21958379)
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J Cell Biol. 2024 Oct 7;223(10):. (PMID: 39078369)
Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):7719-7724. (PMID: 28673977)
BMC Neurosci. 2008 Nov 13;9:112. (PMID: 19014551)
J Neurosci. 2006 Mar 8;26(10):2599-613. (PMID: 16525039)
Hum Mol Genet. 2005 Jun 15;14(12):1613-20. (PMID: 15857855)
PLoS Genet. 2008 Dec;4(12):e1000317. (PMID: 19112491)
J Neurosci. 2004 Feb 4;24(5):1236-44. (PMID: 14762142)
J Neurosci. 2008 May 28;28(22):5731-9. (PMID: 18509034)
J Neurosci. 2008 Dec 31;28(53):14329-40. (PMID: 19118165)
N Engl J Med. 2006 Mar 30;354(13):1370-7. (PMID: 16571880)
J Biol Chem. 2000 Sep 22;275(38):29685-93. (PMID: 10896669)
Nucleic Acids Res. 2018 Jul 2;46(W1):W242-W245. (PMID: 29762716)
J Neurosci. 2010 Jan 20;30(3):1038-48. (PMID: 20089912)
Bioinformatics. 2014 Aug 15;30(16):2389-90. (PMID: 24771516)
Neurology. 2012 Apr 24;78(17):1299-303. (PMID: 22496201)
J Cell Sci. 2019 Jan 16;132(2):. (PMID: 30598502)
Nature. 1995 Nov 2;378(6552):85-8. (PMID: 7477295)
Proc Natl Acad Sci U S A. 2024 Jul 30;121(31):e2310120121. (PMID: 39058579)
Front Cell Neurosci. 2016 Mar 30;10:81. (PMID: 27064559)
J Cell Biol. 2002 Nov 25;159(4):663-72. (PMID: 12438413)
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):14055-9. (PMID: 11698661)
Brain. 2022 Jul 29;145(7):2301-2312. (PMID: 35373813)
Nat Commun. 2023 Oct 26;14(1):6797. (PMID: 37884508)
Nat Commun. 2024 Aug 9;15(1):6801. (PMID: 39122707)
Neuron. 2013 May 8;78(3):469-82. (PMID: 23664614)
Cell Rep. 2022 Mar 15;38(11):110483. (PMID: 35294878)
J Neurosci. 2010 Jul 21;30(29):9738-52. (PMID: 20660256)
Bioessays. 2003 Jun;25(6):542-53. (PMID: 12766944)
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Cell Rep. 2015 Dec 29;13(12):2781-93. (PMID: 26711344)
J Cell Biol. 2000 Jan 10;148(1):147-58. (PMID: 10629225)
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Neuron. 2019 Aug 21;103(4):583-597.e8. (PMID: 31272828)
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Grant Information:
F31 NS134125 United States NS NINDS NIH HHS; F31 NS139435 United States NS NINDS NIH HHS; R35 NS122073 United States NS NINDS NIH HHS
Substance Nomenclature:
0 (Shaker Superfamily of Potassium Channels)
0 (Membrane Proteins)
0 (Kv Channel-Interacting Proteins)
0 (Membrane Proteins)
0 (Kv Channel-Interacting Proteins)
Entry Date(s):
Date Created: 20250523 Date Completed: 20250523 Latest Revision: 20250722
Update Code:
20260130
PubMed Central ID:
PMC12101511
DOI:
10.1126/sciadv.adv1281
PMID:
40408471
Database:
MEDLINE
*Further Information*
*Action potentials are initiated and modulated at the axon initial segment (AIS) by highly clustered ion channels. Voltage-gated Kv1 potassium channels underlie most outward AIS K <sup>+</sup> current. AIS Kv1 channels exist in a large protein complex including ADAM22, Caspr2, and LGI1. However, their clustering mechanisms remain unknown. Because Kv1 channels have a highly conserved PDZ-binding motif, we used CRISPR-based genome editing to screen 18 PDZ domain-containing proteins identified in our previous AIS proximity proteome for their AIS localization. Among these, we found that the scaffolding proteins SCRIB and PSD93 are highly enriched at the AIS. Using CRISPR-mediated knockout, cell surface clustering assays, and coimmunoprecipitation, we show that SCRIB and PSD93 bind to and are required for AIS Kv1 channel clustering, whereas SCRIB links the AIS Kv1 channel protein complex to the master AIS scaffolding protein AnkyrinG. These results define a hierarchy of scaffolding proteins that combine to cluster AIS Kv1 channels.*