Krapivinsky, G., Gordon, E. A., Wickman, K., Velimirovic, B., Krapivinsky, L. & Clapham, D. E. The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K+-channel proteins. Nature 374, 135-141

Mayo Clinic - Rochester, Рочестер, Minnesota, United States
Nature (Impact Factor: 41.46). 04/1995; 374(6518):135-41. DOI: 10.1038/374135a0
Source: PubMed


Heart rate is slowed in part by acetylcholine-dependent activation of a cardiac potassium (K+) channel, IKACh. Activated muscarinic receptors stimulate IKACh via the G-protein beta gamma-subunits. It has been assumed that the inwardly rectifying K(+)-channel gene, GIRK1, alone encodes IKACh. It is now shown that IKACh is a heteromultimer of two distinct inwardly rectifying K(+)-channel subunits, GIRK1 and a newly cloned member of the family, CIR.

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    • "On the other hand, it has been previously shown that expression of either Kir3.1 or Kir3.4 homomers fails to display similar channel activity as the heteromeric complex. Specifically, homomeric expression of Kir3.1 in several mammalian cell lines does not yield detectable currents (e.g., [15] [27] [29]). Furthermore, homomeric expression of Kir3.4 gives several-fold smaller currents than the Kir3.1/Kir3.4 "
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    ABSTRACT: Cholesterol is one of the major lipid components of membranes in mammalian cells. In recent years, cholesterol has emerged as a major regulator of ion channel function. The most common effect of cholesterol on ion channels in general and on inwardly rectifying potassium (Kir) channels in particular is a decrease in activity. In contrast, we have recently shown that native G-protein gated Kir (GIRK or Kir3) channels that underlie atrial KACh currents are up-regulated by cholesterol. Here we unveil the biophysical basis of cholesterol-induced increase in KACh activity. Using planar lipid bilayers we show that cholesterol significantly enhances the channel open frequency of the Kir3.1/Kir3.4 channels, which underlie KACh currents. In contrast, our data indicate that cholesterol does not affect their unitary conductance. Furthermore, using fluorescent and TIRF microscopy as well as surface protein biotinylation, we also show that cholesterol enrichment in vitro has no effect on surface expression of GFP-tagged channels expressed in Xenopus oocytes or transfected into HEK293 cells. Together, these data demonstrate for the first time that cholesterol enhances Kir3-mediated current by increasing the channel open probability. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jul 2015 · Biochimica et Biophysica Acta
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    • "Atrial-specific currents I Kur and I K,ACh are functional in hESC-atrial CMs The potassium ion channels K v 1.5 and the K ir 3.1/3.4 are more abundant in human atrial than in ventricular CMs (Wang et al, 1993; Krapivinsky et al, 1995) and are responsible for functional differences between the two chambers. K v 1.5, encoded by the gene KCNA5, conducts the ultrarapid delayed rectifier K + current, I Kur, which is a major repolarizing current in the human atrium. "
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    ABSTRACT: Drugs targeting atrial-specific ion channels, Kv1.5 or Kir3.1/3.4, are being developed as new therapeutic strategies for atrial fibrillation. However, current preclinical studies carried out in non-cardiac cell lines or animal models may not accurately represent the physiology of a human cardiomyocyte (CM). In the current study, we tested whether human embryonic stem cell (hESC)-derived atrial CMs could predict atrial selectivity of pharmacological compounds. By modulating retinoic acid signaling during hESC differentiation, we generated atrial-like (hESC-atrial) and ventricular-like (hESC-ventricular) CMs. We found the expression of atrial-specific ion channel genes, KCNA5 (encoding Kv1.5) and KCNJ3 (encoding Kir 3.1), in hESC-atrial CMs and further demonstrated that these ion channel genes are regulated by COUP-TF transcription factors. Moreover, in response to multiple ion channel blocker, vernakalant, and Kv1.5 blocker, XEN-D0101, hESC-atrial but not hESC-ventricular CMs showed action potential (AP) prolongation due to a reduction in early repolarization. In hESC-atrial CMs, XEN-R0703, a novel Kir3.1/3.4 blocker restored the AP shortening caused by CCh. Neither CCh nor XEN-R0703 had an effect on hESC-ventricular CMs. In summary, we demonstrate that hESC-atrial CMs are a robust model for pre-clinical testing to assess atrial selectivity of novel antiarrhythmic drugs. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    Full-text · Article · Feb 2015 · EMBO Molecular Medicine
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    • "that early interactions with signaling partners such as Gβγ play in channel maturation remain unclear. When expressed alone, recombinant Kir3.1, which contains only one potential site for Nlinked glycosylation, migrates as a doublet with a molecular mass of 54 and 56 kDa, with the upper band being the core-glycosylated, immature form of the protein (Krapivinsky et al., 1995a; Kennedy et al., 1999). Upon treatment with either endoglycosidase H, an enzyme that selectively removes N-linked glycosyl moieties from proteins that have not been processed in the Golgi, or endoglycosidase F, an enzyme that non-selectively removes all N-linked sugar residues, the 56 kDa band is virtually abolished, confirming its residence in the ER (Kennedy et al., 1999). "
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    ABSTRACT: The role of Gβγ subunits in Kir3 channel gating is well characterized. Here, we have studied the role of Gβγ dimers during their initial contact with Kir3 channels, prior to their insertion into the plasma membrane. We show that distinct Gβγ subunits play an important role in orchestrating and fine-tuning parts of the Kir3 channel life cycle. Gβ1γ2, apart from its role in channel opening that it shares with other Gβγ subunit combinations, may play a unique role in protecting maturing channels from degradation as they transit to the cell surface. Taken together, our data suggest that Gβ1γ2 prolongs the lifetime of the Kir3.1/Kir3.2 heterotetramer, although further studies would be required to shed more light on these early Gβγ effects on Kir3 maturation and trafficking.
    Full-text · Article · Apr 2014 · Frontiers in Cellular Neuroscience
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