AUTHOR=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 

TITLE=Identification of IQM-266, a Novel DREAM Ligand That Modulates KV4 Currents

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=12

YEAR=2019

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2019.00011

DOI=10.3389/fnmol.2019.00011

ISSN=1662-5099

ABSTRACT=<p>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 (<italic>I</italic><sub>A</sub>). This effect is mediated by the interaction between DREAM and K<sub>V</sub>4 potassium channels and it has been shown that small molecules that bind to DREAM modify channel function. A-type outward potassium current (<italic>I</italic><sub>A</sub>) 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<sub>V</sub>4.3/DREAM channels, we have identified IQM-266 as a DREAM ligand. IQM-266 inhibited the K<sub>V</sub>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 (<inline-formula><mml:math id="M1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msub><mml:mtext>Q</mml:mtext><mml:mrow><mml:msub><mml:mtext>K</mml:mtext><mml:mtext>V</mml:mtext></mml:msub><mml:mn>4.3</mml:mn><mml:mo>/</mml:mo><mml:mtext>DREAM</mml:mtext></mml:mrow></mml:msub></mml:mrow></mml:math></inline-formula>) 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<sub>V</sub>4.3/DREAM channels. Finally, in rat dorsal root ganglion neurons, IQM-266 inhibited the peak amplitude and slowed the inactivation of <italic>I</italic><sub>A</sub>. 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 <italic>I</italic><sub>A</sub> in pathological processes.</p>