Activation of TRESK background potassium channels by cloxyquin exerts protective effects against excitotoxic-induced brain injury and neuroinflammation in neonatal rats

Dilek, Mustafa; Kılınc, Yasemin Baranoglu; Kılınç, Erkan; Torun, İbrahim Ethem; Şaylan, Aslıhan; Düzcü, Selma Erdoğan

doi:10.1016/j.jneuroim.2022.577894

Cited by 5 publications

(1 citation statement)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To understand the hTRESK / cloxyquin interaction in more detail, we utilized different techniques including TEVC measurements in Xenopus laevis oocytes, which is a well-established, highly robust and versatile method for functional and pharmacological evaluation of membrane proteins 52 , 53 . Heterologous expression in these oocytes can also provide limited insights into intracellular mechanisms, however, further secondary effects of TRESK channel modulation should be evaluated within more physiological models as previously performed in other studies 27 , 29 , 30 , 54 .…”

Section: Discussionmentioning

confidence: 99%

Cloxyquin activates hTRESK by allosteric modulation of the selectivity filter

et al. 2023

View full text Add to dashboard Cite

The TWIK-related spinal cord K+ channel (TRESK, K2P18.1) is a K2P channel contributing to the maintenance of membrane potentials in various cells. Recently, physiological TRESK function was identified as a key player in T-cell differentiation rendering the channel a new pharmacological target for treatment of autoimmune diseases. The channel activator cloxyquin represents a promising lead compound for the development of a new class of immunomodulators. Identification of cloxyquin binding site and characterization of the molecular activation mechanism can foster the future drug development. Here, we identify the cloxyquin binding site at the M2/M4 interface by mutational scan and analyze the molecular mechanism of action by protein modeling as well as in silico and in vitro electrophysiology using different permeating ion species (K+ / Rb+). In combination with kinetic analyses of channel inactivation, our results suggest that cloxyquin allosterically stabilizes the inner selectivity filter facilitating the conduction process subsequently activating hTRESK.

show abstract