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      Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

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          Abstract

          The voltage-gated potassium channel Kv1.5, which mediates the cardiac ultra-rapid delayed-rectifier ( I Kur) current in human cells, has a crucial role in atrial fibrillation. Therefore, the design of selective Kv1.5 modulators is essential for the treatment of pathophysiological conditions involving Kv1.5 activity. This review summarizes the progress of molecular structures and the functionality of different types of Kv1.5 modulators, with a focus on clinical cardiovascular drugs and a number of active natural products, through a summarization of 96 compounds currently widely used. Furthermore, we also discuss the contributions of Kv1.5 and the regulation of the structure-activity relationship (SAR) of synthetic Kv1.5 inhibitors in human pathophysiology. SAR analysis is regarded as a useful strategy in structural elucidation, as it relates to the characteristics that improve compounds targeting Kv1.5. Herein, we present previous studies regarding the structural, pharmacological, and SAR information of the Kv1.5 modulator, through which we can assist in identifying and designing potent and specific Kv1.5 inhibitors in the treatment of diseases involving Kv1.5 activity.

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          The voltage-gated potassium channels and their relatives.

          Gary Yellen (2002)
          The voltage-gated potassium channels are the prototypical members of a family of membrane signalling proteins. These protein-based machines have pores that pass millions of ions per second across the membrane with astonishing selectivity, and their gates snap open and shut in milliseconds as they sense changes in voltage or ligand concentration. The architectural modules and functional components of these sophisticated signalling molecules are becoming clear, but some important links remain to be elucidated.
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            Cardiac potassium channel subtypes: new roles in repolarization and arrhythmia.

            Nicole Schmitt, Morten Grunnet, Søren-Peter Olesen (2014)
            About 10 distinct potassium channels in the heart are involved in shaping the action potential. Some of the K+ channels are primarily responsible for early repolarization, whereas others drive late repolarization and still others are open throughout the cardiac cycle. Three main K+ channels drive the late repolarization of the ventricle with some redundancy, and in atria this repolarization reserve is supplemented by the fairly atrial-specific KV1.5, Kir3, KCa, and K2P channels. The role of the latter two subtypes in atria is currently being clarified, and several findings indicate that they could constitute targets for new pharmacological treatment of atrial fibrillation. The interplay between the different K+ channel subtypes in both atria and ventricle is dynamic, and a significant up- and downregulation occurs in disease states such as atrial fibrillation or heart failure. The underlying posttranscriptional and posttranslational remodeling of the individual K+ channels changes their activity and significance relative to each other, and they must be viewed together to understand their role in keeping a stable heart rhythm, also under menacing conditions like attacks of reentry arrhythmia.
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              Expression and function of the K+ channel KCNQ genes in human arteries.

              Marcus Reddy, Antonio Nardi, Maksym Harhun … (2010)
              KCNQ-encoded voltage-gated potassium channels (K(v) 7) have recently been identified as important anti-constrictor elements in rodent blood vessels but the role of these channels and the effects of their modulation in human arteries remain unknown. Here, we have assessed KCNQ gene expression and function in human arteries ex vivo. Fifty arteries (41 from visceral adipose tissue, 9 mesenteric arteries) were obtained from subjects undergoing elective surgery. Quantitative RT-PCR experiments using primers specific for all known KCNQ genes and immunohistochemsitry were used to show K(v) 7 channel expression. Wire myography and single cell electrophysiology assessed the function of these channels. KCNQ4 was expressed in all arteries assessed, with variable contributions from KCNQ1, 3 and 5. KCNQ2 was not detected. K(v) 7 channel isoform-dependent staining was revealed in the smooth muscle layer. In functional studies, the K(v) 7 channel blockers, XE991 and linopirdine increased isometric tension and inhibited K(+) currents. In contrast, the K(v) 7.1-specific blocker chromanol 293B did not affect vascular tone. Two K(v) 7 channel activators, retigabine and acrylamide S-1, relaxed preconstricted arteries, actions reversed by XE991. K(v) 7 channel activators also suppressed spontaneous contractile activity in seven arteries, reversible by XE991. This is the first study to demonstrate not only the presence of KCNQ gene products in human arteries but also their contribution to vascular tone ex vivo. This article is commented on by Mani and Byron, pp. 38-41 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.01065.x. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biomolecules
                Journal ID (iso-abbrev): Biomolecules
                Journal ID (publisher-id): biomolecules
                Title: Biomolecules
                Publisher: MDPI
                ISSN (Electronic): 2218-273X
                Publication date (Electronic): 19 December 2019
                Publication date Collection: January 2020
                Volume: 10
                Issue: 1
                Electronic Location Identifier: 10
                Affiliations
                [1 ]Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, 229 Taibai Road, Xi’an 710069, China; zzf598155752@ 123456sina.com (Z.Z.); ruansongsong@ 123456stumail.nwu.edu.cn (S.R.); 201720920@ 123456stumail.nwu.edu.cn (X.M.); fengqian@ 123456stumail.nwu.edu.cn (Q.F.); 18821657783@ 123456163.com (Z.X.); nz19980217@ 123456163.com (Z.N.); f568902@ 123456163.com (P.F.); yongmin.zhang@ 123456upmc.fr (Y.Z.); zhengxh@ 123456nwu.edu.cn (X.Z.)
                [2 ]Biomedicine Key Laboratory of Shaanxi Province, School of Pharmacy, Northwest University, 229 Taibai Road, Xi’an 710069, China
                [3 ]Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou 213164, China; mqian2019@ 123456cczu.edu.cn
                [4 ]Laboratory for Medicinal Chemistry, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium
                [5 ]Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, China; xiruihe@ 123456163.com
                [6 ]Sorbonne Université, Institut Parisien de Chimie Moléculaire, CNRS UMR 8232, 4 place Jussieu, 75005 Paris, France
                Author notes
                [* ]Correspondence: wushaoping@ 123456nwu.edu.cn ; Tel.: +86-029-88304569
                Author information
                https://orcid.org/0000-0001-6235-7687
                https://orcid.org/0000-0001-8493-5812
                Article
                Publisher ID: biomolecules-10-00010
                DOI: 10.3390/biom10010010
                PMC ID: 7022446
                PubMed ID: 31861703
                SO-VID: b48ca44c-114c-48c5-8e84-f473b3a67e88
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 13 November 2019
                Date accepted : 10 December 2019
                Categories
                Subject: Review

                Keywords: potassium channel,kv1.5,kcna5,modulators,sar
                Data availability:
                Keywords: potassium channel, kv1.5, kcna5, modulators, sar

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