Chemical tolls to modulate kchip3 signaling

Abstract

DREAM (Downstream Regulatory Element Antagonist Modulator), also known as KChIP-3 or calsenilin, is a multifunctional calcium binding protein that controls the expression level and/or the activity of several proteins related to calcium homeostasis, neuronal excitability and neuronal survival. As an auxiliary protein in the plasma membrane, DREAM interacts with KV4 potassium channels, L- and T-type voltage-dependent calcium channels, NMDA receptors, presenilins and the transcriptor factor ATF6.1 The interaction between DREAM and KV4 potassium channels regulates of A-type outward potassium currents (IA) that is responsible of the fast repolarization of neuron action potentials and frequency of firing.2 Using a multidisciplinary approach that involves drug design, organic chemistry, surface plasmon resonance assays, electrophysiological recordings of KV4.3/DREAM channels, and IA recordings in rat dorsal root ganglion neurons, we have identified IQM-266.3 IQM-266 slows the inactivation kinetics, and this effect may explain why at concentrations lower than the IC50, IQM-266 augments the efflux of potassium ions resulting in an increase of the charge (activating effect). This effect could be the basis of a promising therapeutic strategy for the treatment of certain neuronal pathologies (epilepsy, Alzheimer disease or ataxia), in which a downregulation of KV4.3 or DREAM has been demonstrated.4 IQM-266 also modulated IA from rat DRG neurons. Overall, IQM-266 constitutes a novel small chemical tool suitable to modulate KV4.3 channels in native systems, that might allow a better understanding of DREAM physiological roles, as well as modulation of neuronal IA current in pathological processes.