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

Benito-Bueno, Angela de; Socuéllamos, Paula G.; Merinero, Yaiza G.; Cercós, Pilar; Izquierdo, Carolina; Daniel-Mozo, Miguel; Marín-Olivero, Irene; Pérez-Lara, Ángel; González‐Vera, Juan A.; Orte, Ángel; Albert, Armando; Martı́n-Martı́nez, Mercedes; Gutiérrez-Rodríguez, Marta; Valenzuela, Carmen

doi:10.3390/ijms23169170

Cited by 4 publications

(2 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They also identified IQM-266 as a novel KChIP3 ligand with similar inhibitory properties to IQM-PC330 and IQM-PC332 [64]. Recently, IQM-266 was reported to bind KChIP2 and increase KV4.3/KChIP2 currents [65].…”

Section: Kchip Ligands Affect Kchip Regulation On Kv4mentioning

confidence: 95%

KV Channel-Interacting Proteins in Neurological and Cardiovascular System: An Updated Review

Wu¹,

Song²,

Zhang³

et al. 2023

Preprint

View full text Add to dashboard Cite

KV channel-interacting proteins (KChIPs) belong to a family of Ca2+-binding EF-hand proteins that are able to bind to the N-terminus of the KV4 channel α-subunits. As the auxiliary subunit, KChIPs are critically involved in regulating the amplitude and gating properties of KV4 channels by modulating their cell surface trafficking, voltage-dependent activation, inactivation kinetics, and recovery rate from inactivation. IKs, ICa,L, and INa can also be regulated by KChIPs. KChIPs are predominantly expressed in the brain and heart, where they contribute to the maintenance of the excitability of neurons and cardiomyocytes by modulating the KV4 currents. Interestingly, all KChIPs can act as transcription factors to control the expression of genes involved in pain, memory, and circadian regulation. Altered expression of KChIPs has been implicated in the pathogenesis of many diseases, such as arrhythmia, heart failure, Alzheimer's disease, etc. In this review, we summarize the research progress of KChIPs in their structural properties, physiological functions, and pathological roles in disease progression, and provide an overview of the therapeutic potential of KChIPs as pharmacological targets for associated disorders.

show abstract

Section: Kchip Ligands Affect Kchip Regulation On Kv4mentioning

confidence: 95%

KV Channel-Interacting Proteins in Neurological and Cardiovascular System: An Updated Review

Wu¹,

Song²,

Zhang³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…They also identified IQM-266 as a novel KChIP3 ligand with similar inhibitory properties to IQM-PC330 and IQM-PC332 [76]. Recently, IQM-266 was reported to bind KChIP2 and increase K V 4.3/KChIP2 currents [77].…”

Section: Role Of Kchips In Regulating Other Ion Channelsmentioning

confidence: 95%

KV Channel-Interacting Proteins in the Neurological and Cardiovascular Systems: An Updated Review

Song

Zhang

et al. 2023

Cells

View full text Add to dashboard Cite

KV channel-interacting proteins (KChIP1-4) belong to a family of Ca2+-binding EF-hand proteins that are able to bind to the N-terminus of the KV4 channel α-subunits. KChIPs are predominantly expressed in the brain and heart, where they contribute to the maintenance of the excitability of neurons and cardiomyocytes by modulating the fast inactivating-KV4 currents. As the auxiliary subunit, KChIPs are critically involved in regulating the surface protein expression and gating properties of KV4 channels. Mechanistically, KChIP1, KChIP2, and KChIP3 promote the translocation of KV4 channels to the cell membrane, accelerate voltage-dependent activation, and slow the recovery rate of inactivation, which increases KV4 currents. By contrast, KChIP4 suppresses KV4 trafficking and eliminates the fast inactivation of KV4 currents. In the heart, IKs, ICa,L, and INa can also be regulated by KChIPs. ICa,L and INa are positively regulated by KChIP2, whereas IKs is negatively regulated by KChIP2. Interestingly, KChIP3 is also known as downstream regulatory element antagonist modulator (DREAM) because it can bind directly to the downstream regulatory element (DRE) on the promoters of target genes that are implicated in the regulation of pain, memory, endocrine, immune, and inflammatory reactions. In addition, all the KChIPs can act as transcription factors to repress the expression of genes involved in circadian regulation. Altered expression of KChIPs has been implicated in the pathogenesis of several neurological and cardiovascular diseases. For example, KChIP2 is decreased in failing hearts, while loss of KChIP2 leads to increased susceptibility to arrhythmias. KChIP3 is increased in Alzheimer’s disease and amyotrophic lateral sclerosis, but decreased in epilepsy and Huntington’s disease. In the present review, we summarize the progress of recent studies regarding the structural properties, physiological functions, and pathological roles of KChIPs in both health and disease. We also summarize the small-molecule compounds that regulate the function of KChIPs. This review will provide an overview and update of the regulatory mechanism of the KChIP family and the progress of targeted drug research as a reference for researchers in related fields.

show abstract

Novel insights intoI_Kurmodulation by Lgi3-4: Implications in atrial fibrillation

Socuéllamos,

Macías,

de Benito-Bueno

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: Patients with atrial fibrillation (AF) exhibit a reduction in the ultrarapid outward potassium current (IKur) conducted by Kv1.5 channels. Ion channels are modulated by regulatory subunits, forming channelosomes. One such regulatory family are leucine-rich glioma-inactivated proteins (Lgi1-4), which interact with and modulate Kv1 in neurons. However, their impact in the heart remains unknown. We investigated the role of Lgi proteins in cardiac electrophysiology, focusing on IKur, and their contribution to the pathophysiology of AF. Methods: We used three complementary biological systems, including cell lines, AAV-mediated cardiac-specific Lgi4 mice (Lgi4 mice), and human samples from patients in sinus rhythm (SR) and AF. Our multidisciplinary approach included immunolocalization, patch-clamp, surface ECG, intracardiac stimulation, and molecular biology techniques. Results: Only Lgi3 and Lgi4 were expressed in human heart. In human atrium and heterologous cells, Lgi3 and Lgi4 interacted with Kv1.5 channels. In HEK293 cells, Lgi3-4 impaired Kv1.5/Kvβ association, partially reversing the Kvβ-induced N-type inactivation and reducing IKur amplitude. On surface ECG, the QRS interval was prolonged, and impulse conduction was impaired in Lgi4 mice compared to control. In isolated ventricular cardiomyocytes from Lgi4 mice, early action potential repolarization was prolonged compared to control. These results correlated with the reduced Kv1.5 membrane expression and IKur density observed in Lgi4 cardiomyocytes and HEK293 cells. Notably, Lgi4 protein expression was lower in atrial tissue from patients with AF than SR. The reduction of Lgi4 in AF was associated with an altered colocalization with Kv1.5 channels, suggesting potential disruptions in their functional interactions. Conclusions: Lgi3-4 proteins are new components of KV1.5 channelosome. They modulate IKur by interfering with Kv1.5 interaction with Kvβ. Importantly, Lgi4 is dysregulated differently in paroxysmal versus permanent AF. The results improved the understanding of this most common type of arrhythmia and identified Lgi proteins as a new potential target for AF treatment.

show abstract

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

Cited by 4 publications

References 49 publications

KV Channel-Interacting Proteins in Neurological and Cardiovascular System: An Updated Review

KV Channel-Interacting Proteins in Neurological and Cardiovascular System: An Updated Review

KV Channel-Interacting Proteins in the Neurological and Cardiovascular Systems: An Updated Review

Novel insights intoI_Kurmodulation by Lgi3-4: Implications in atrial fibrillation

Contact Info

Product

Resources

About

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

Cited by 4 publications

References 49 publications

KV Channel-Interacting Proteins in Neurological and Cardiovascular System: An Updated Review

KV Channel-Interacting Proteins in Neurological and Cardiovascular System: An Updated Review

KV Channel-Interacting Proteins in the Neurological and Cardiovascular Systems: An Updated Review

Novel insights intoIKurmodulation by Lgi3-4: Implications in atrial fibrillation

Contact Info

Product

Resources

About

Novel insights intoI_Kurmodulation by Lgi3-4: Implications in atrial fibrillation