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

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_V4 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_V4.3/DREAM channels, we have identified IQM-266 as a DREAM ligand. IQM-266 inhibited the K_V4.3/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 ( ${\text{Q}}_{{\text{K}}_{\text{V}}4.3/\text{DREAM}}$ ) 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_V4.3/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.

A-type current; Alzheimer; DREAM; DREAM ligands; KChIP; KV4.3 channels.