ArticleThe Journal of biological chemistry2008
Role of S3 and S4 transmembrane domain charged amino acids in channel biogenesis and gating of KCa2.3 and KCa3.1.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 36 citations in OpenAlex.
- VX-445 (elexacaftor) inhibits chloride secretion across human bronchial epithelial cells by directly blocking KCa3.1 channels.PNAS nexus · 2025Article
- Characterization of two pathological gating-charge substitutions in Cav1.4 L-type calcium channels.Channels (Austin, Tex.) · 2023Article
- The exocyst complex is required for the trafficking and delivery of KCa3.1 to the basolateral membrane of polarized epithelia.American journal of physiology. Cell physiology · 2023Article
- Histone deacetylase inhibitors (HDACi) increase expression of KCa2.3 (SK3) in primary microvascular endothelial cells.American journal of physiology. Cell physiology · 2022Article
- Role of SNARE Proteins in the Insertion of KCa3.1 in the Plasma Membrane of a Polarized Epithelium.Frontiers in physiology · 2022Article
- Plasma membrane insertion of KCa2.3 (SK3) is dependent upon the SNARE proteins, syntaxin-4 and SNAP23.PloS one · 2018Article
- Structure, Gating and Basic Functions of the Ca2+-activated K Channel of Intermediate Conductance.Current neuropharmacology · 2018Review
- Modulation of Retrograde Trafficking of KCa3.1 in a Polarized Epithelium.Frontiers in physiology · 2017Article
- The large conductance calcium-activated potassium channel affects extrinsic and intrinsic mechanisms of apoptosis.Journal of neuroscience research · 2015Article
- AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension.Science signaling · 2014Article
- Anterograde trafficking of KCa3.1 in polarized epithelia is Rab1- and Rab8-dependent and recycling endosome-independent.PloS one · 2014Article
- Trafficking of intermediate (KCa3.1) and small (KCa2.x) conductance, Ca(2+)-activated K(+) channels: a novel target for medicinal chemistry efforts?ChemMedChem · 2012Review
- Role of Derlin-1 protein in proteostasis regulation of ATP-sensitive potassium channels.The Journal of biological chemistry · 2012Article
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- Role of ubiquitylation and USP8-dependent deubiquitylation in the endocytosis and lysosomal targeting of plasma membrane KCa3.1.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2011Article
- Involvement of dominant-negative spliced variants of the intermediate conductance Ca2+-activated K+ channel, K(Ca)3.1, in immune function of lymphoid cells.The Journal of biological chemistry · 2011Article
- The Cavβ subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels.Nature neuroscience · 2011Article
- Role of the ubiquitin system in regulating ion transport.Pflugers Archiv : European journal of physiology · 2011Article
- ESCRT-dependent targeting of plasma membrane localized KCa3.1 to the lysosomes.American journal of physiology. Cell physiology · 2010Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The role of positively charged arginines in the fourth transmembrane domain (S4) and a single negatively charged amino acid in the third transmembrane domain (S3) on channel biogenesis and gating of voltage-gated K(+) channels (Kv) has been well established. Both intermediate (KCa3.1) and small (KCa2.x) conductance, Ca(2+)-activated K(+) channels have two conserved arginines in S4 and a single conserved glutamic acid in S3, although these channels are voltage-independent. We demonstrate that mutation of any of these charged amino acids in KCa3.1 or KCa2.3 to alanine, glutamine, or charge reversal mutations results in a rapid degradation (<30 min) of total protein, confirming the critical role of these amino acids in channel biogenesis. Mutation of the S4 arginine closest to the cytosolic side of KCa3.1 to histidine resulted in expression at the cell surface. Excised patch clamp experiments revealed that this Arg/His mutation had a dramatically reduced open probability (P(o)), relative to wild type channels. Additionally, we demonstrate, using a combination of short hairpin RNA, dominant negative, and co-immunoprecipitation studies, that both KCa3.1 and KCa2.3 are translocated out of the endoplasmic reticulum associated with Derlin-1. These misfolded channels are poly-ubiquitylated, recognized by p97, and targeted for proteasomal degradation. Our results suggest that S3 and S4 charged amino acids play an evolutionarily conserved role in the biogenesis and gating of KCa channels. Furthermore, these improperly folded K(+) channels are translocated out of the endoplasmic reticulum in a Derlin-1- and p97-dependent fashion, poly-ubiquitylated, and targeted for proteasomal degradation.
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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.