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Chemical tolls to modulate kchip3 signaling

AuthorsIzquierdo García, Carolina; Peraza, Diego A.; Cercós, Pilar CSIC; Miaja, Pablo; Merinero, Yaiza G.; Lagartera, L.; Socuéllamos, Paula G.; Martín-Martínez, Mercedes CSIC ORCID; Olivos-Oré, Luis Alcides; Naranjo, José Ramón; Artalejo, Antonio R.; Valenzuela, Carmen CSIC ORCID CVN; Gutiérrez-Rodríguez, Marta CSIC ORCID
Issue Date8-Jul-2019
Citation19th Meeting SEQT (2019)
AbstractDREAM (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.
DescriptionTrabajo presentado en el 19th Meeting SEQT, celebrado en Vitoria-Gasteiz (España) del 8 al 11 de julio de 2019.
Appears in Collections:(IIBM) Comunicaciones congresos
(IQM) Comunicaciones congresos
(CNB) Comunicaciones congresos

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