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Disease Associated Mutations in KIR Proteins Linked to Aberrant Inward Rectifier Channel Trafficking

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Disease Associated Mutations in KIR Proteins Linked to Aberrant Inward Rectifier Channel Trafficking biomolecules Review Disease Associated Mutations in KIR Proteins Linked to Aberrant Inward Rectifier Channel Trafficking 1, 2, 2 1 Eva-Maria Zangerl-Plessl y, Muge Qile y, Meye Bloothooft , Anna Stary-Weinzinger and Marcel A. G. van der Heyden 2,* 1 Department of Pharmacology and Toxicology, University of Vienna, 1090 Vienna, Austria; [email protected] (E.-M.Z.-P.); [email protected] (A.S.-W.) 2 Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, 3584 CM Utrecht, The Netherlands; [email protected] (M.Q.); [email protected] (M.B.) * Correspondence: [email protected]; Tel.: +31-887558901 These authors contributed equally to this work. y Received: 28 August 2019; Accepted: 23 October 2019; Published: 25 October 2019 Abstract: The ubiquitously expressed family of inward rectifier potassium (KIR) channels, encoded by KCNJ genes, is primarily involved in cell excitability and potassium homeostasis. Channel mutations associate with a variety of severe human diseases and syndromes, affecting many organ systems including the central and peripheral neural system, heart, kidney, pancreas, and skeletal muscle. A number of mutations associate with altered ion channel expression at the plasma membrane, which might result from defective channel trafficking. Trafficking involves cellular processes that transport ion channels to and from their place of function. By alignment of all KIR channels, and depicting the trafficking associated mutations, three mutational hotspots were identified. One localized in the transmembrane-domain 1 and immediately adjacent sequences, one was found in the G-loop and Golgi-export domain, and the third one was detected at the immunoglobulin-like domain. Surprisingly, only few mutations were observed in experimentally determined Endoplasmic Reticulum (ER)exit-, export-, or ER-retention motifs. Structural mapping of the trafficking defect causing mutations provided a 3D framework, which indicates that trafficking deficient mutations form clusters. These “mutation clusters” affect trafficking by different mechanisms, including protein stability. Keywords: inward rectifier channel; trafficking; alignment; mutation; KCNJ;KIR; disease; structure 1. Introduction Seventy years ago, Katz detected the inward rectification phenomenon for the first time [1]. Its unexpected property of conducting larger inward than outward potassium currents at similar deviations from the potassium equilibrium potential was unprecedented at that time. During the following decades, the understanding of inward rectifier channels was established further, stimulated by biophysical analysis and cloning of KIR genes. Inward rectifying channels—unlike voltage-gated potassium channels (Kv) which open in response to alterations in transmembrane electrostatic potential [2,3]—are primarily gated by intracellular substances (e.g., polyamines and Mg2+). Spermine and spermidine—two polyamines for which micromolar concentrations are sufficient to reach physiological effective levels—cause stronger block of the outward current than Mg2+. The underlying molecular mechanism of rectification was first explained by Lopatin in 1994 [3]. Polyamines enter the channel pore from the cytoplasmic side and subsequently interact with six specific residues (i.e., KIR2.1 E224, D259, E299, F254, D255 and D172) [4] in the transmembrane pore domain and its cytosolic pore extension. A similar mechanism of pore-blocking is caused by Mg2+, but weaker. Biomolecules 2019, 9, 650; doi:10.3390/biom9110650 www.mdpi.com/journal/biomolecules Biomolecules 2019, 9, x 2 of 15 domain and its cytosolic pore extension. A similar mechanism of pore-blocking is caused by Mg2+, but weaker. The inward rectifier channel family consists of strong and weak rectifiers. Strong rectifiers, e.g., Biomolecules 2019, 9, 650 2 of 15 KIR2 and KIR3, are often expressed in excitable cells such as neuronal or muscle cells. Their rectifying properties enable cells to conserve K+ during action potential formation and facilitate K+ entry upon cell hyperpolarization.The inward rectifier In addition, channel family they contribute consists of to strong repolarization and weak rectifiers.and stabilization Strong rectifiers, of the resting e.g., μ membraneKIR2 and potential. KIR3, are often For example, expressed application in excitable of cells 10 suchM barium, as neuronal at that or muscleconcentration cells. Their rather rectifying specific + + forproperties KIR2 channel enable inhibition, cells to conserve lengthened K during the action action potential potential formation of guinea-pig and facilitate papillary K entry muscle upon preparationscell hyperpolarization. by 20 ms [5]. In In addition, the heart, they K contributeIR2 is strongly to repolarization expressed in and the stabilization ventricles and of the less resting in the atrioventricularmembrane potential. node (AVN) For example, [6]; KIR application3 is mainly of expressed 10 µM barium, in the at atrium that concentration with much lower rather levels specific in for the ventricle.KIR2 channel Weak inhibition, rectifier channels, lengthened e.g., the actionKIR1, K potentialIR4, and of K guinea-pigIR5, are mainly papillary associated muscle preparationswith potassium by homeostasis20 ms [5]. Inand the often heart, regulate KIR2 is stronglyextracellular expressed potassiu in them concentrations ventricles and less to allow in the atrioventricularfunctioning of several node ion(AVN) (co)transporters. [6]; KIR3 is mainly expressed in the atrium with much lower levels in the ventricle. Weak rectifier channels, e.g., K 1, K 4, and K 5, are mainly associated with potassium homeostasis and often KIR channels areIR encodedIR by IRKCNJ genes. Various diseases associate with mutations in KCNJ genes.regulate The extracellularaim of this review potassium is to concentrations correlate disease to allow associated functioning mutations of several causing ion (co)transporters. aberrant inward K channels are encoded by KCNJ genes. Various diseases associate with mutations in KCNJ rectifier channelIR trafficking with protein domains important for trafficking by means of channel genes. The aim of this review is to correlate disease associated mutations causing aberrant inward alignment, and finally to put mutational changes in a structural framework. rectifier channel trafficking with protein domains important for trafficking by means of channel alignment, and finally to put mutational changes in a structural framework. 2. Classification, Structure, and Expression 2.The Classification, KIR family Structure,is divided andinto Expressionseven subfamilies (KIR1-7) according to their amino-acid homology [4]. TheThe sequence KIR family homology is divided is 40% into between seven subfam subfamiliesilies and (K IRrises1-7) to according 70% within to theirsome amino-acidsubfamilies. Thehomology structural [4 common]. The sequence features homology of these channels is 40% between are that subfamilies the channel and pore rises is formed to 70% withinby a tetramer some of subfamilies.subunits, most The often structural homotetramers common features (Figure of these1). Each channels subunit are thathas thetwo channel transmembrane pore is formed domains by (M1a tetramerand M2) of which subunits, are most separated often homotetramers by a pore-loop (Figure that1 ).contains Each subunit the GYG has two(or transmembraneGFG) potassium selectivitydomains filter (M1 andmotif M2) located which areclose separated to the extrac by a pore-loopellular side that of contains the membrane. the GYG (or Pore-loop GFG) potassium stability dependsselectivity strongly filter on motif one located negatively close and to theone extracellular positively charged side of residue, the membrane. E138 and Pore-loop R148 respectively stability in dependsKIR2.1 [7]. strongly There is on a onerelatively negatively short and N-terminus one positively linked charged to M1 residue, and a longer E138 and C-terminus R148 respectively linked to M2in which KIR2.1 form [7]. Therethe characteristic is a relatively cytoplasmic short N-terminus extend linkeded pore to domain M1 and (CTD). a longer Despite C-terminus their linkedstructural to similarities,M2 which the form KIR the subfamilies characteristic also cytoplasmic display divergent extended properti pore domaines, e.g., (CTD). sensitivity Despite to extracellular their structural Ba2+ 2+ or similarities,the response the to K regulatoryIR subfamilies signals. also display divergent properties, e.g., sensitivity to extracellular Ba or the response to regulatory signals. Figure 1. Two opposing domains of the KIR channel with structural common features highlighted. Figure 1. Two opposing domains of the KIR channel with structural common features The membrane is indicated by dotted lines. The selectivity filter (SF) is highlighted by a dotted box. highlighted. The membrane is indicated by dotted lines. The selectivity filter (SF) is Ions inside the SF are shown as green spheres. Residues E138 and R148 (KIR2.1) are shown as spheres. Biomolecules 2019, 9, x 3 of 15 highlighted by a dotted box. Ions inside the SF are shown as green spheres. Residues E138 and R148 (KIR2.1) are shown as spheres. Biomolecules 2019, 9, 650 3 of 15 All KIR family members have a widespread expression pattern [4]. Neural tissues strongly express KIR2, KIR3, KIR4, and KIR5. Kidneys show high expression of KIR4, KIR5, and KIR6, whereas All KIR family members have a widespread expression pattern [4]. Neural tissues strongly express pancreatic tissue
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