Identification of IQM-266, a Novel DREAM Ligand That Modulates KV 4 Currents

Frontiers in Molecular Neuroscience
Diego A PerazaCarmen Valenzuela

Abstract

Downstream Regulatory Element Antagonist Modulator (DREAM)/KChIP3/calsenilin is a neuronal calcium sensor (NCS) with multiple functions, including the regulation of A-type outward potassium currents (IA). This effect is mediated by the interaction between DREAM and KV4 potassium channels and it has been shown that small molecules that bind to DREAM modify channel function. A-type outward potassium current (IA) is responsible of the fast repolarization of neuron action potentials and frequency of firing. Using surface plasmon resonance (SPR) assays and electrophysiological recordings of KV4.3/DREAM channels, we have identified IQM-266 as a DREAM ligand. IQM-266 inhibited the KV4.3/DREAM current in a concentration-, voltage-, and time-dependent-manner. By decreasing the peak current and slowing the inactivation kinetics, IQM-266 led to an increase in the transmembrane charge ( Q K V 4.3 / DREAM ) at a certain range of concentrations. The slowing of the recovery process and the increase of the inactivation from the closed-state inactivation degree are consistent with a preferential binding of IQM-266 to a pre-activated closed state of KV4.3/DREAM channels. Finally, in rat dorsal root ganglion neurons, IQM-266 inhibited t...Continue Reading

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Citations

May 16, 2019·Scientific Reports·Alejandro Lopez-HurtadoMarta Gutierrez-Rodriguez
Feb 13, 2021·International Journal of Molecular Sciences·Pilar CercósMarta Gutiérrez-Rodríguez

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Methods Mentioned

BETA
surface plasmon resonance
chip

Software Mentioned

Clampfit
SPR
PCLAMP
BIAevaluation X - 100
PatchMaster
Origin

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