International Journal of Molecular Sciences Review Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs Pilar Cercós 1, Diego A. Peraza 2,3 , Angela de Benito-Bueno 2,3 , Paula G. Socuéllamos 2,3, Abdoul Aziz-Nignan 4, Dariel Arrechaga-Estévez 4, Escarle Beato 4, Emilio Peña-Acevedo 4, Armando Albert 5 , Juan A. González-Vera 6 , Yoel Rodríguez 4 , Mercedes Martín-Martínez 1 , Carmen Valenzuela 2,3,* and Marta Gutiérrez-Rodríguez 1,* 1 Instituto de Química Médica (IQM-CSIC), 28006 Madrid, Spain; [email protected] (P.C.); [email protected] (M.M.-M.) 2 Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), CSIC-UAM, 28029 Madrid, Spain; [email protected] (D.A.P.); [email protected] (A.d.B.-B.); [email protected] (P.G.S.) 3 Spanish Network for Biomedical Research in Cardiovascular Research (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain 4 Department of Natural Sciences, Hostos Community College of CUNY, New York, NY 10451, USA; [email protected] (A.A.-N.); [email protected] (D.A.-E.); [email protected] (E.B.); [email protected] (E.P.-A.); [email protected] (Y.R.) 5 Instituto de Química Física Rocasolano (IQFR-CSIC), 28006 Madrid, Spain; [email protected] 6 Departamento de Físicoquímica, Facultad de Farmacia, Universidad de Granada, 18071 Granada, Spain; [email protected] * Correspondence: [email protected]; (C.V.); [email protected] (M.G.-R.); Tel.: +34-91-585-4493 (C.V.); +34-91-258-7493 (M.-G.R.) Citation: Cercós, P.; Peraza, D.A.; Abstract: Ion channels are macromolecular complexes present in the plasma membrane and in- Benito-Bueno, A.d.; Socuéllamos, P.G.; tracellular organelles of cells. Dysfunction of ion channels results in a group of disorders named Aziz-Nignan, A.; Arrechaga-Estévez, channelopathies, which represent an extraordinary challenge for study and treatment. In this review, D.; Beato, E.; Peña-Acevedo, E.; we will focus on voltage-gated potassium channels (KV), specifically on the KV4-family. The activa- Albert, A.; González-Vera, J.A.; et al. tion of these channels generates outward currents operating at subthreshold membrane potentials as Pharmacological Approaches for the recorded from myocardial cells (ITO, transient outward current) and from the somata of hippocampal Modulation of the Potassium Channel neurons (ISA). In the heart, KV4 dysfunctions are related to Brugada syndrome, atrial fibrillation, KV4.x and KChIPs. Int. J. Mol. Sci. hypertrophy, and heart failure. In hippocampus, K 4.x channelopathies are linked to schizophrenia, 2021, 22, 1419. https://doi.org/ V 10.3390/ijms22031419 epilepsy, and Alzheimer’s disease. KV4.x channels need to assemble with other accessory subunits (β) to fully reproduce the ITO and ISA currents. β Subunits affect channel gating and/or the traffic to Academic Editor: the plasma membrane, and their dysfunctions may influence channel pharmacology. Among KV4 Antonio Ferrer-Montiel regulatory subunits, this review aims to analyze the KV4/KChIPs interaction and the effect of small Received: 16 January 2021 molecule KChIP ligands in the A-type currents generated by the modulation of the KV4/KChIP Accepted: 28 January 2021 channel complex. Knowledge gained from structural and functional studies using activators or Published: 31 January 2021 inhibitors of the potassium current mediated by KV4/KChIPs will better help understand the under- lying mechanism involving KV4-mediated-channelopathies, establishing the foundations for drug Publisher’s Note: MDPI stays neutral discovery, and hence their treatments. with regard to jurisdictional claims in published maps and institutional affil- Keywords: voltage-gated potassium channels KV4; transient outward current; A-type current; potas- iations. sium channel interacting proteins (KChIPs); protein–protein interactions; KV4/KChIPs modulators Copyright: © 2021 by the authors. 1. Introduction Licensee MDPI, Basel, Switzerland. Ion channels are macromolecular complexes present in the plasma membrane and in- This article is an open access article tracellular organelles of all cells. They play an important role in the maintenance of cellular distributed under the terms and integrity, smooth muscle contraction, secretion of hormones, and neurotransmitters, among conditions of the Creative Commons Attribution (CC BY) license (https:// others. Dysfunction of ion channels results in a group of disorders named channelopathies, creativecommons.org/licenses/by/ which represent an extraordinary challenge for study and treatment [1]. 4.0/). Int. J. Mol. Sci. 2021, 22, 1419. https://doi.org/10.3390/ijms22031419 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 21 cellular integrity, smooth muscle contraction, secretion of hormones, and neurotransmit- Int. J. Mol. Sci. 2021,ters,22, 1419 among others. Dysfunction of ion channels results in a group of disorders named 2 of 21 channelopathies, which represent an extraordinary challenge for study and treatment [1]. In this review, we will focus on voltage-gated potassium channels (KV), specifically on the KV4-family or Shal-related subfamily. Four members compose this family: KV4.1 In this review, we will focus on voltage-gated potassium channels (KV), specifically (KCND1), KV4.2 (KCND2), and two splice variants of KV4.3 (KCND3), which have an over- on the KV4-family or Shal-related subfamily. Four members compose this family: KV4.1 all sequence identity of 60% [2,3]. As with other eukaryotic KV channels, KV4.x are sym- (KCND1), K 4.2 (KCND2), and two splice variants of K 4.3 (KCND3), which have an metrically assembled as homoV - or heterotetramers of pore-forming subunitsV (α subunits) over-all sequence identity of 60% [2,3]. As with other eukaryotic K channels, K 4.x around a central pore [4,5]. Each of these α subunits have six transmembrane helices V(S1– V are symmetrically assembled as homo- or heterotetramers of pore-forming subunits (α S6), with its N- and C-terminus pointing to the cytoplasm. At the N-terminus, the princi- subunits) around a central pore [4,5]. Each of these α subunits have six transmembrane pal motif is the so-called T1 domain, which governs the specificity of assembly and is helices (S1–S6), with its N- and C-terminus pointing to the cytoplasm. At the N-terminus, involved in channel tetramerization and its gating. The first four helices (S1–S4) form the the principal motif is the so-called T1 domain, which governs the specificity of assembly voltage-sensing domain, whereas S5, S6, and the P-loop that link them, form the pore do- and is involved in channel tetramerization and its gating. The first four helices (S1–S4) main. There is homogeneity within the KV4.x transmembrane region, except in the S6- form the voltage-sensing domain, whereas S5, S6, and the P-loop that link them, form the proximal cytosolic C-terminus, where KV4.3 isoform 1 has an additional exon that encodes pore domain. There is homogeneity within the KV4.x transmembrane region, except in 19 amino acids (residues 488–506) (Figure 1). Owing to alternative splicing of this addi- the S6-proximal cytosolic C-terminus, where KV4.3 isoform 1 has an additional exon that tional exon, KVencodes4.3 has two 19 amino variants acids in human (residues tissues: 488–506) KV4.3L (Figure (long1). form) Owing and to K alternativeV4.3S (short splicing of this form). Both splice variants are identical except for the additional sequence of 19 amino additional exon, KV4.3 has two variants in human tissues: KV4.3L (long form) and KV4.3S acids present in(short the long form). form Both KV4.3L splice [6,7]. variants are identical except for the additional sequence of 19 KV4 channels are highly expressed in smooth muscles, heart, and brain. The activa- amino acids present in the long form KV4.3L [6,7]. tion of these channels generates outward currents operating at subthreshold membrane KV4 channels are highly expressed in smooth muscles, heart, and brain. The activa- potentials, as tionrecorded of these from channels myocardial generates cells (I outwardTO, transient currents outward operating current) at subthreshold and from membrane the somata of hippocampal neurons (ISA, somato-dendritic subthreshold-activating A-type potentials, as recorded from myocardial cells (ITO, transient outward current) and from the + V V V + K current) [3,8,9]somata. Among of hippocampal K 4 channels, neurons K 4.2 (IandSA, K somato-dendritic4.3 are the most subthreshold-activatingthoroughly studied A-type K members of thecurrent) family. [ 3Concerning,8,9]. Among the K Vmyocardium,4 channels, K KVV4.24.2 and and K KVV4.34.3 arepresent the most a comple- thoroughly studied mentary expression,members with of K theV4.2 family. being Concerningmore abundant the myocardium,in the ventricle K Vand4.2 andKV4.3 K Vin4.3 the present a com- atria [8,9]. In theplementary heart, KV4 expression, dysfunctions with are K involvedV4.2 being in moreBrugada abundant syndrome, in the atrial ventricle fibri- and KV4.3 in llation, hypertrophythe atria, and [8, 9heart]. In failure the heart, [10]. K V4 dysfunctions are involved in Brugada syndrome, atrial In the brain,fibri-llation, the KV4 channel hypertrophy, expression and heartdepends failure on the [10 ].neuron type and region, and continuous efforts areIn themade brain, to unravel the KV4 the channel organization expression of these depends channels on the in neuron different type sub- and region, and cellular compartmentscontinuous and efforts neuron are madetypes to [11,12]. unravel In the hippocampus, organization of K theseV4 channelopathies channels in different subcellu- are linked to schizophrenia,lar compartments epilepsy and neuron, and Alzheimer’s types [11,12]. disease In hippocampus, [13–15]. Hence, KV4 channelopathies the phar- are linked macological modulationto schizophrenia, of ITO and epilepsy, ISA may and have Alzheimer’s therapeutic disease value in [13 the–15 treatment].