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

• Published in: Frontiers in molecular neuroscience Vol. 12; p. 11
• Main Authors: Peraza, Diego A, Cercós, Pilar, Miaja, Pablo, Merinero, Yaiza G, Lagartera, Laura, Socuéllamos, Paula G, Izquierdo García, Carolina, Sánchez, Sara A, López-Hurtado, Alejandro, Martín-Martínez, Mercedes, Olivos-Oré, Luis A, Naranjo, José R, Artalejo, Antonio R, Gutiérrez-Rodríguez, Marta, Valenzuela, Carmen
• Format: Journal Article
• Language: English
• Published: Switzerland 2019
• Subjects: DREAM; KChIP; DREAM ligands; A-type current; Alzheimer; KV4.3 channels
• ISSN: 1662-5099; 1662-5099

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 (
). This effect is mediated by the interaction between DREAM and K
4 potassium channels and it has been shown that small molecules that bind to DREAM modify channel function. A-type outward potassium current (
) 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
4.3/DREAM channels, we have identified IQM-266 as a DREAM ligand. IQM-266 inhibited the K
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 (
) 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
4.3/DREAM channels. Finally, in rat dorsal root ganglion neurons, IQM-266 inhibited the peak amplitude and slowed the inactivation of
. 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
in pathological processes.