RT Journal Article
T1 Identification of IQM-266, a Novel DREAM Ligand that Modulates Kv4 Currents
T2 Identificación de IQM-266, un nuevo ligando DREAM que modula las corrientes Kv4
A1 Peraza, Diego
A1 Cercos, Pilar
A1 Miaja, Pablo
A1 Merinero, Yaiza
A1 Lagartera, Laura
A1 Socuéllamos, Paula
A1 Izquierdo, Carolina
A1 Sánchez, Sara
A1 López-Hurtado, Alejandro
A1 Martín-Martínez, Mercedes
A1 Olivos Ore, Luis Alcides
A1 Naranjo, José
A1 Rodríguez Artalejo, Antonio
A1 Gutiérrez Rodríguez, Marta
A1 Valenzuela, Carmen
AB 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 KV4 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 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 ( QKV4.3/DREAMQKV4.3/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 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.
PB Frontiers media SA
SN 1662-5099
YR 2019
FD 2019
LK https://hdl.handle.net/20.500.14352/94886
UL https://hdl.handle.net/20.500.14352/94886
LA eng
NO Spanish Ministry of Economy, Industry and Competitivity (Ministerio de Economía y Competitividad; AEI-FEDER, EU grants)
NO Universidad Complutense de Madrid (UCM)
NO Instituto de Salud Carlos III CIBERNED and CIBERCV programs
NO Madrid regional government/Neurodegmodels
NO Consejo Superior de Investigaciones Científicas (CSIC)
DS Docta Complutense
RD 10 abr 2025