期刊
FRONTIERS IN MOLECULAR NEUROSCIENCE
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fnmol.2019.00011
关键词
K(V)4.3 channels; DREAM; DREAM ligands; KChIP; A-type current; Alzheimer
资金
- Spanish Ministry of Economy, Industry and Competitivity (MINECO)
- Spanish Ministry of Economy, Industry and Competitivity (Ministerio de Economia y Competitividad
- AEI-FEDER, EU grants) [SAF2012-32209, BFU2015-67284-R, SAF2014-53412-R, SAF2017-89554-R, SAF2013-45800-R, SAF2016-75021-R, SAF2015-66275-C2-2-R]
- Universidad Complutense de Madrid (UCM) grant [PR75/18-21593]
- Instituto de Salud Carlos III CIBERNED program
- Instituto de Salud Carlos III CIBERCV program
- Madrid regional government/Neurodegmodels
- Consejo Superior de Investigaciones Cientificas (CSIC) [PIE 201820E104, 201880E109]
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 (I-A). This effect is mediated by the interaction between DREAM and K(V)4 potassium channels and it has been shown that small molecules that bind to DREAM modify channel function. A-type outward potassium current (I-A) is responsible of the fast repolarization of neuron action potentials and frequency of firing. Using surface plasmon resonance (SPR) assays and electrophysiological recordings of K(V)4.3/DREAM channels, we have identified IQM-266 as a DREAM ligand. IQM-266 inhibited the K(V)4.3/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(KV)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 K(V)4.3/DREAM channels. Finally, in rat dorsal root ganglion neurons, IQM-266 inhibited the peak amplitude and slowed the inactivation of I-A. Overall, the results presented here identify IQM-266 as a new chemical tool that might allow a better understanding of DREAM physiological role as well as modulation of neuronal I-A in pathological processes.
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