Discovery of a small molecule modulator of the Kv1.1/Kvβ1 channel complex that reduces neuronal excitability and in vitro epileptiform activity

Abstract

Summary Aims Kv1.1 (KCNA1) channels contribute to the control of neuronal excitability and have been associated with epilepsy. Kv1.1 channels can associate with the cytoplasmic Kvβ1 subunit resulting in rapid inactivating A‐type currents. We hypothesized that removal of channel inactivation, by modulating Kv1.1/Kvβ1 interaction with a small molecule, would lead to decreased neuronal excitability and anticonvulsant activity. Methods We applied high‐throughput screening to identify ligands able to modulate the Kv1.1‐T1 domain/Kvβ1 protein complex. We then selected a compound that was characterized on recombinant Kv1.1/Kvβ1 channels by electrophysiology and further evaluated on sustained neuronal firing and on in vitro epileptiform activity using a high K+‐low Ca2+ model in hippocampal slices. Results We identified a novel compound able to modulate the interaction of the Kv1.1/Kvβ1 complex and that produced a functional inhibition of Kv1.1/Kvβ1 channel inactivation. We demonstrated that this compound reduced the sustained repetitive firing in hippocampal neurons and was able to abolish the development of in vitro epileptiform activity. Conclusions This study describes a rational drug discovery approach for the identification of novel ligands that inhibit Kv1.1 channel inactivation and provides pharmacological evidence that such a mechanism translates into physiological effects by reducing in vitro epileptiform activity.

LGI1 downregulation increases neuronal circuit excitability

“…To conclude, the results reported here demonstrate that a subacute decrease of LGI1 can result in alterations of the DG-CA3 pathway excitability and increases in network hyperexcitability in vitro. Our findings support new pathophysiological mechanisms by which alteration of LGI1 affects brain excitability and opens up new clinical intervention routes through, for example, the use of small molecules that increase Kv1.1 inactivation (Niespodziany et al, 2019).…”

LGI1 downregulation increases neuronal circuit excitability

“…Our findings support new pathophysiological mechanisms by which alteration of LGI1 affects brain excitability and opens up new clinical intervention routes through, for example, the use of small molecules that inhibit Kv1.1 inactivation. 46…”

Transient receptor potential vanilloid 4 activation inhibits the delayed rectifier potassium channels in hippocampal pyramidal neurons: An implication in pathological changes following pilocarpine‐induced status epilepticus

“…Epilepsy gene therapy targeting KCNA1 s uppresses seizures in TLE rat models (Snowball et al., 2019). Inhibition of Kv1.1 channels inactivation reduces neuronal excitability and epileptiform activity (Niespodziany et al., 2019). Decreasing the expression of Kv1.2 channels or mutations of KCNB1 resulting in the loss of Kv2.1 channels enhances the intrinsic excitability and leads to the development of epilepsy (Thiffault et al., 2015; Zhou et al., 2018).…”