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

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.

IQM-PC332, a Novel DREAM Ligand with Antinociceptive Effect on Peripheral Nerve Injury-Induced Pain

“…This would relate to its ability to perturb DREAM-ion channel interactions at the plasma membrane. IQM-PC332 modulation of I A in DRG neurons is consistent with previous data indicating that IQM-PC332 binds to DREAM and silences DREAM's effect on Kv4.3 channels expressed in CHO cells [20,21]. Likewise, the effect of IQM-PC332 on HVA Ca v channels could be related to the fact that DREAM (KChIP3) coimmunoprecipitates with HVA Ca v 1.2 (L-type) channels and that IQM-PC332 blocks (IC 50 of 32.64 nM) such a DREAM-Ca v channel interaction (J.R.N, personal communication).…”

“…Here we investigated the mechanical antinociceptive effect of the a novel DREAM ligand IQM-PC332 (2-[2- (3,acetylamino]-4-(4 -n-butylphenyl)benzoic acid) in rats subjected to chronic constriction injury of the sciatic nerve (CCI), a common model of post-traumatic neuropathic pain. IQM-PC332 is known to bind with high affinity to DREAM (K D = 0.28 µM in the surface plasmon resonance assay) and to inhibit currents through K v 4.3/DREAM channels expressed in African green monkey kidney-derived CHO-K1 (CHO) cells with an IC 50 = 6.8 µM [20,21]. Here, we show that IQM-PC332 exerts an antinociceptive effect upon local and systemic administration.…”

“…It seems therefore plausible that by binding to DREAM, IQM-PC332 could inhibit T-type Ca v channels directly or indirectly through K v 4.3 channels [16,52]. IQM-PC332 has been proposed to interact with multiple residues of DREAM (Leu96, Phe100, Ile117, Tyr118, Phe121, Tyr130, Phe151, Leu155, Leu158, Leu159, Ile194 and Ile256), which are mostly located in a large hydrophobic cavity surrounded by the N-and C-terminus of the protein [20,21]. Interestingly, both the N- [13,14] and C-terminus [52] of DREAM interact with ion channels, hence making it possible for IQM-PC332 to affect those interactions.…”

“…IQM-PC332 has been characterized as an inhibitor of K v 4.3/DREAM channels expressed in a heterologous system [20,21]. Since DRG neurons express DREAM as well as K v 4.3 channels, which contribute to I A [14,22,23], we first set out to record I A in DRG neurons from unoperated, Control, animals to evaluate the effect of IQM-PC332 on native potassium channels.…”

Modulation of KV4.3-KChIP2 Channels by IQM-266: Role of DPP6 and KCNE2

“…However, to fully reproduce the I tof current, K V 4 channels need to assemble with other accessory subunits forming channelosomes . These protein complexes can be formed by different regulatory (or β) subunits, including KChIPs (potassium channel interacting proteins), DPPs (dipeptidyl-peptidase-like proteins), KCNEs (also termed MinK-related peptides, or MiRPs), KChAPs and K V βx subunits [ 14 , 15 , 16 , 17 , 18 , 19 ].…”