Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs.

Pilar Cercós,Angela De Benito-Bueno,Marta Gutiérrez-Rodríguez,Abdoul Aziz-Nignan,Yoel Rodríguez,Armando Albert,Dariel Arrechaga-Estévez,Carmen Valenzuela,Escarle Beato,Mercedes Martín-Martínez,Paula G Socuéllamos,Juan A González-Vera,Emilio Peña-Acevedo,Diego A Peraza

doi:10.3390/ijms22031419

Abstract

Ion channels are macromolecular complexes present in the plasma membrane and intracellular organelles of cells. Dysfunction of ion channels results in a group of disorders named channelopathies, which represent an extraordinary challenge for study and treatment. In this review, we will focus on voltage-gated potassium channels (KV), specifically on the KV4-family. The activation of these channels generates outward currents operating at subthreshold membrane potentials as recorded from myocardial cells (ITO, transient outward current) and from the somata of hippocampal neurons (ISA). In the heart, KV4 dysfunctions are related to Brugada syndrome, atrial fibrillation, hypertrophy, and heart failure. In hippocampus, KV4.x channelopathies are linked to schizophrenia, 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 the plasma membrane, and their dysfunctions may influence channel pharmacology. Among KV4 regulatory subunits, this review aims to analyze the KV4/KChIPs interaction and the effect of small molecule KChIP ligands in the A-type currents generated by the modulation of the KV4/KChIP channel complex. Knowledge gained from structural and functional studies using activators or inhibitors of the potassium current mediated by KV4/KChIPs will better help understand the underlying mechanism involving KV4-mediated-channelopathies, establishing the foundations for drug discovery, and hence their treatments.

Highlights

This review aims to analyze the KV4/KChIPs interaction and the effect of small molThis review aims to analyze the K 4/KChIPs interaction and the effect of small ecule KChIP ligands in the A-type currents generated byVthe modulation of the KV4/KChIP
After the assembly of KV 4.x channels with KChIP subunits, these regulatory subunits induce an increase in the traffic of KV 4.x channels to the plasma membrane, a delay in the macroscopic inactivation kinetics, and an acceleration of both the activation and the recovery kinetics from inactivation of KV 4.x channels (Figure 5) [3,36]
It was shown that arachidonic acid (AA) decreases the maximum peak amplitude of the currents generated by neuronal, KV 4.3, and KV 4.3+KChIP1 channels, with the greater effect being on KV 4.2/KChIP1

Summary

Introduction

We will focus on voltage-gated potassium channels (K ), (KCND1), KV4.2 (KCND2), and two splice variants of KV4.3 (KCND3), which have an over-V on the K 4-family or Shal-related subfamily. Four members compose this family: KV 4.1 all sequence identity ofV 60% [2,3]. 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 doand is involved in channel tetramerization and its gating. To establish the bases of drug discovery to treat them

Potassium

Three-Dimensional Structures of Free KChIPs

KChIP Ligands

Findings

Concluding Remarks