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Inwardly Rectifying Potassium Channel Genes & Diseases (2021) 8, 272e278 Available online at www.sciencedirect.com ScienceDirect journal homepage: http://ees.elsevier.com/gendis/default.asp REVIEW ARTICLE Inwardly rectifying potassium channel 5.1: Structure, function, and possible roles in diseases Junhui Zhang a,b,f,1, Jian Han c,1, Lingfei Li d, Qiong Zhang a,b, Yanhai Feng a,b, Youzhao Jiang e, Fang Deng f, Yuping Zhang f, Qinan Wu g, Bing Chen f,**, Jiongyu Hu a,b,f,* a Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China b State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China c Department of Obstetrics and Gynecology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, PR China d Department of Dermatology, Daping Hospital, Third Military Medical University (Army Medical University), Chongqing, 400042, PR China e Department of Endocrinology, People’s Hospital of Banan District, Chongqing, 401320, PR China f Department of Endocrinology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China g Department of Endocrinology, Chongqing Cancer Hospital (Chongqing University Cancer Hospital), Chongqing, 40030, PR China Received 27 November 2019; received in revised form 2 March 2020; accepted 13 March 2020 Available online 21 March 2020 þ KEYWORDS Abstract Inwardly rectifying potassium (Kir) channels make it easier for K to enter into a Cancer; cell and subsequently regulate cellular biological functions. Kir5.1 (encoded by KCNJ16) alone Cardiovascular can form a homotetramer and can form heterotetramers with Kir4.1 (encoded by KCNJ10)or Kir4.2 (encoded by KCNJ15). In most cases, homomeric Kir5.1 is non-functional, while hetero- disease; þ Cochlea; meric Kir5.1 on the cell membrane contributes to the inward flow of K ions, which can be Kir5.1 regulated by intracellular pH and a variety of signaling mechanisms. In the form of a * Corresponding author. Endocrinology Department, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Gaotanyan Street, Shapingba District, Chongqing 400038, China. ** Corresponding author. Department of Endocrinology, Southwest Hospital, Third Military Medical University (Army Medical University), Gaotanyan Street, Shapingba District, Chongqing, 400038, China. E-mail addresses: [email protected] (B. Chen), [email protected] (J. Hu). Peer review under responsibility of Chongqing Medical University. 1 These authors contributed equally to this work. https://doi.org/10.1016/j.gendis.2020.03.006 2352-3042/Copyright ª 2020, Chongqing Medical University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Rectifying potassium channel 5.1 273 heterotetramer, Kir5.1 regulates Kir4.1/4.2 activity and is involved in the maintenance of heterotetramer; nephron function. Actually, homomeric Kir5.1 may also play a very important role in diseases, Ventilatory response including in the ventilatory response to hypoxia and hypercapnia, hearing impairment, cardio- vascular disease and cancer. With an increase in the number of studies into the roles of Kir channels, researchers are paying more attention to the pathophysiological functions of Kir5.1. This minireview provides an overview regarding these Kir5.1 roles. Copyright ª 2020, Chongqing Medical University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/). Introduction transmembrane domains (TM1 and TM2) connected with an extracellular pore-forming region (H5) and cytoplasmic 15,16 It is well known that maintaining an electrochemical amino (NH2)- and carboxy (COOH)-terminal domains. imbalance across the plasma membrane is an essential The H5 region functions as an “ion-selectivity filter” that 1 shares the characteristic sequence T-X-G-Y(F)-G with other cellular biological process. A large number of integral þ 11,17 membrane proteins play roles in facilitating ion transport K -selective ion channels. The NH2 and COOH termini across membranes,2,3 and among these, the family of are considered gating regulators, and the C-terminal cyto- inwardly rectifying potassium (Kir) channels is expressed in solic domain, located downstream of the H5 region, is rich b almost all human cells and plays critical roles in the regu- in -sheets and provides binding sites where multiple lation of potassium balance, maintenance of negative intracellular signaling regulators interact (Fig. 1B). These binding sites are highly conserved and are important for resting potential, regulation of cell volume, clearance of 18,19 extracellular glutamate, regulation of myelination and inward rectification. control of cellular excitability.4,5 Commonly, four subunits with two TM domains each are Kir channels were first verified as anomalous rectifier Kþ necessary for the formation of a functional Kir channel in a 6,7 þ tetrameric complex, which can be either homomeric or current channels. They make it easier for K to enter into 20 rather than exit a cell; i.e., instead of conducting Kþ ions by heteromeric. Generally, heteromerized Kir channels are depolarization, as is the case of other Kþ channels, Kir found in members of the same subfamily; for instance, þ Kir3.1 can associate with other Kir3.x subfamily members, channels transport K ions on the basis of hyperpolarization. 21 Kir channels have multiple physiological functions, depend- such as Kir3.2 or Kir3.4. An exception is Kir4.1, which can ing on their type and location, and their activities are assemble with Kir5.1. Coexpression studies have demon- controlled by a variety of mediators, such as binding pro- strated that Kir5.1 forms functional heteromeric complexes with Kir4.1 (encoded by KCNJ10) to construct novel Kir4.1/ teins, phospholipids and ions. Kir channel subunits contain 2,16,22 two transmembrane domains linked with the characteristic Kir5.1 channels. Homomeric Kir5.1 expressed in the Kþ-selective pore sequence, and they can be assembled into heterologous expression systems, unlike the heteromeric homotetramers or heterotetramers. Since the first discovery Kir4.1/Kir5.1 complexe that is stable and functional on the of Kir1.1 in 1993, approximately fifteen distinct clones have plasma membrane of various cells, was promptly exocy- tosed and internalized across the membrane surface and been identified, and they can be divided into seven major 23 subfamilies (Kir1.xeKir7.x, where x is the number of each was unable to yield any currents. In addition to hetero- member) and four functional subgroups: ATP-sensitive Kþ merization with Kir4.1, Kir5.1 may also form a heteromeric channels, classic Kir channels, Kþ-transport channels and G complex with Kir4.2 (encoded by KCNJ15), which is a close homolog of Kir4.1 and is widely distributed in the brain, protein-gated Kir channels. In general, their physiological 24,25 roles have either been established or proposed. kidney, lung, liver and pancreas. To date, no other However, the Kir5.x family is an exception. To date, Kir5.1 channel has been demonstrated to form functional chan- (encoded by KCNJ16) is the only identified member of this nels with Kir5.1. The mechanisms by which Kir4.1 and Kir4.2 family. As a Kþ-transport channel, Kir5.1 mRNA has been rescue the function of Kir5.1 remain unknown. found in the brain region, cochlea, kidney, thyroid, stomach, liver, pancreas, adrenal gland, spleen, testis, and para- The Kir4.1/Kir5.1 heterotetramer acts as the 8e14 thyroid gland. With the increase in the number of studies predominant potassium channel in distal into the roles of Kir channels, researchers are paying greater nephron segments attention to the pathophysiological functions of Kir5.1. This minireview aims to provide an overview regarding the func- þ tions of Kir5.1 and its potential roles in diseases. K channels play important roles in regulating renal ion transportation directly by providing a secretory pathway for Kþ or indirectly by modulating Kþ recycling across the Basic molecular structure and primary function plasma membrane and controlling the membrane poten- of Kir5.1 tial.26,27 Heteromeric Kir4.1/Kir5.1 channels are widely found in the principal cells of the cortical thick ascending The primary structure of Kir5.1 is common to all Kir chan- limb (TAL), distal convoluted tubule (DCT), and cortical nels (Fig. 1A). It contains a common motif of two putative collecting duct (CCD).1 The basolateral location of 274 J. Zhang et al. Figure 1 Genomic and structural organization of KCNJ16/Kir5.1. (A) Basic structure of Kir5.1. Each Kir subunit contains two transmembrane (TM1 and TM2) regions, a pore-forming (H5) loop, and cytosolic NH2 and COOH termini. (B) Exons of the mRNA and amino distribution of KCNJ16/Kir5.1 were retrieved from Uniprot database.66 Kir4.1/Kir5.1 channels indicates their role in the mainte- elevation of Kþ conductance in the basolateral membrane, nance of basolateral membrane potential and in the enhances basolateral ClÀ outflow, leads to hyperchloremia “recycling” of the Kþ that enters a cell via basolateral and acidosis, elevates the activities of Naþ-Kþ-ATPase and Naþ/Kþ ATPase. It has been shown that the recycling of NCC (sodium
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