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Review
. 2021 Jan 31;22(3):1419.
doi: 10.3390/ijms22031419.

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 , Marta Gutiérrez-Rodríguez  1
Affiliations
Review

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

Pilar Cercós et al. Int J Mol Sci. .

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.

Keywords: A-type current; KV4/KChIPs modulators; potassium channel interacting proteins (KChIPs); protein–protein interactions; transient outward current; voltage-gated potassium channels KV4.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Alignment of human KV4. Alignment with Clustal within Jalview. Residues that are identical in the four sequences are boxed [16].
Figure 2
Figure 2
Alignment of human KChIPs. Alignment with ClustalO within Jalview. Residues that are identical in the four sequences are boxed [16].
Figure 3
Figure 3
Three-dimensional structures of free KChIPs. The four EF-hand motifs are shown, as representative examples: (A) KChIP3 (PDB ID 2JUL) [51] and (B) KChIP4a (PDB ID 3DD4) [52]. Different from KChIP1-3, KChIP4a C-terminal α-helix H10 (red) swings outward at ~45° from the hydrophobic pocket. Ca2+ ions are shown as yellow spheres.
Figure 4
Figure 4
Three-dimensional structures of KChIPs–KV4 complexes. (A) KChIP1(34–216)–KV4.2N30 complex structure (PDB ID 1S6C) showing the four EF-hand motifs (helices H2–H9) and the central hydrophobic pocket occupied by H10 (red) and KV4.2N30 (light blue) helices [53]. (B) Left panel: Overall structure of the KChIP1–KV4.3 T1 complex as seen from the cytosolic side (PDB ID 2I2R) [55]. KChIP1s are shown in dark blue and KV4.3 members are shown in white. Ca2+ ions are shown as yellow spheres and Zn2+ ions are shown in orange. Boxes represent interaction site 1 and interaction site 2. Top right panel: Interaction site 1 showing KChIP1 in dark blue and KV4.3 T1N helix, T1N linker, and T1 domain in white. Ca2+ ions are shown as yellow spheres. Bottom right panel: Interaction site 2 showing the main interface KChIP1(34–216)-KV4.2N30 residues. KChIP1 in dark blue and KV4.2N30 residues in white.
Figure 5
Figure 5
Original KV4.3 (A) and KV4.3+KChIP3 (B) records generated after applying the pulse protocol shown in the upper part of the Figure. Note that KV4.3+KChIP3 channels exhibit a slower inactivation rate than KV4.3 ones.
Figure 6
Figure 6
Cartoon and surface representation of (A) KChIP1 (PDB ID 2I2R) residues suggested by molecular modeling to be involved in CL-888 binding [59]. (B) KChIP3 (PDB ID 2JUL) residues suggested by molecular modeling to participate in 8-anilino-1-naphthalene sulfonate (1,8- ANS) binding [62].
Figure 7
Figure 7
Binding site of IQM-PC330 and IQM-PC332 [69]. (A) Cartoon representation of the molecular docking complex of KChIP3 bound to IQM-PC330 (right) and IQM-PC332 (left). (B) Direct binding of IQM-PC330 and IQM-PC332 in surface plasmon resonance (SPR) assays to immobilized wtKChIP3 compared with Tyr118Ala and Tyr130Ala KChIP3 mutants. (C) Electrophysiological effects of IQM-PC330 and IQM-PC332 on KV4.3/KChIP3 wt and KV4.3/KChIP3 mutant channels. Data are shown as mean ± SEM. * p < 0.05 vs. block produced in KV4.3/DREAM wt channels; ** p < 0.01 vs. block produced in KV4.3/DREAM wt channels; *** p < 0.001 vs. block produced in KV4.3/DREAM wt channels.
Figure 8
Figure 8
Electrophysiological effects of IQM-PC330 on KV4.3 and KV4.3/KChIP3 channels [69]. (A) Bar chart comparing the inhibition of KV4.3/KChIP3 currents produced by IQM-PC330, measured at the maximum peak current and at the charge. Inset shows original current recordings. (B) Original normalized current records: control (black line) and with IQM-PC330 (blue line). (C) Left panel shows current recordings elicited by the recovery protocol shown in the top. Right panel shows the effects of IQM-PC330 on the recovery process. Dashed lines represent the recovery process of KV4.3 current without KChIP3. Note that IQM-PC330 slows the recovery process, reverting KChIP3 effects. Data are shown as mean ± SEM. * p < 0.05; ** p < 0.01.
Figure 9
Figure 9
Concentration–dependence of inhibition and/or increase of the current or the charge through KV4.3/KChIP3 channels produced by IQM-266 [70]. (A) Concentration–response curve of the effects of IQM-266 (continuous line) on KV4.3/KChIP3 channels. The dashed line represents the fit of the data to a Hill equation with nH = 1 (n = 34). (B) Effects on the current induced by IQM-266 in KV4.3/KChIP3 channels at the peak current and in the charge (measured as the area of the current after applying 250 ms pulses to +60 mV; n = 34). (C) Current records of KV4.3/KChIP3 to +60 mV in the absence and in the presence of IQM-266 (3 μM). (D) Current records of KV4.3/KChIP3 to +60 mV in the absence and in the presence of IQM-266 (10 μM). * p < 0.05 when comparing the effect of IQM-266 on the peak current and on the charge through KV4.3/KChIP3 channels.
Figure 10
Figure 10
IQM-266 increases the closed-state inactivation of the KV4.3/KChIP3 channels [70]. (A) Current records generated by KV4.3/KChIP3 channels in the absence and in the presence of IQM-266 after applying the pulse protocols shown in the upper part of the figure. (B) Time course of closed-state inactivation of KV4.3/KChIP3 channels at a membrane potential (−40 mV) at which this current inactivates, but does not conduct. Note how IQM-266 increases the closed-state inactivation.
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