PhD Scientific Days 2017

Oral Presentations: Pharmaceutical

Cloxyquin (5-chloroquinolin-8-ol) is a selective and state dependent activator of TRESK background K+ channel

Előadó neve

Lengyel, Miklós

Előadó munkahelye

Department of Physiology, Semmelweis University, Budapest

Előadó telefonszáma

06-20-294-77-23

Előadó e-mail címe

lengyel.miklos@med.semmelweis-univ.hu

Az előadás címe

Cloxyquin (5-chloroquinolin-8-ol) is a selective and state dependent activator of TRESK background K+ channel

Szerző(k) neve és munkahelye

Miklós Lengyel
Department of Physiology, Semmelweis University, Budapest

Szekció

Oral Presentations: Pharmaceutical

Data of the presenter

Doctoral School: Doctoral School of Molecular Medicine
Doctoral Program: Cellular and Molecular Physiology
Supervisor: Péter Enyedi
E-mail: lengyel.miklos@med.semmelweis-univ.hu

Text of the abstract

Introduction:
K2P leak K+ channels are major determinants of the resting membrane potential and regulate cellular excitability. TRESK background K+ channel is highly expressed in primary somatosensory neurons. TRESK is activated by dephosphorylation by the Ca2+/calmodulin-sensitive phosphatase calcineurin. Investigation of the physiological role of TRESK has been impeded by a lack of specific TRESK modulators.
Aims:
Cloxyquin was an identified as an activator of TRESK in a recent high-throughput study. We planned to investigate the specificity of the cloxyquin effect and to analyze the mechanism of cloxyquin-mediated TRESK activation.
Methods:
K2P channels were expressed in Xenopus oocytes and K+ currents were measured by two-electrode voltage clamp. Dorsal root ganglion (DRG) neurons were isolated from adult mice and K+ currents were measured by whole-cell patch clamp.
Results:
Cloxyquin (100 μM) activated mouse TRESK 4.4±0.3-fold (n=28, EC50=26.4 μM) and the human channel 3.9±0.3-fold (n=8, EC50=43.9 μM). The drug selectively targeted TRESK in the K2P channel family, and this effect was state-dependent: TRESK was efficiently activated by cloxyquin in the resting state. However, the compound did not influence and only marginally affected the mouse and human channel, respectively which had been already activated by the physiological way; Gq-coupled receptors, calcium signal and calcineurin. The constitutively active mutant, mimicking the dephosphorylated state mTRESK-(S276A) or another one containing altered (activating) channel pore mutations (F156A and F364A), were not stimulated further by cloxyquin. In a subpopulation of isolated DRG neurons cloxyquin substantially activated the background K+ current.
Conclusions:
Cloxyquin activates TRESK by a Ca2+/calcineurin-independent mechanism. The drug is specific for TRESK within the K2P channel family and useful for studying TRESK currents in native cells. The state-dependent pharmacological profile of the channel may be considered in the development of therapeutics for nociceptive disorders.
TRESK: TWIK-related spinal cord K+ channel

Kind

Szabad

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

1251

Authors (legacy)

Miklós Lengyel
Department of Physiology, Semmelweis University, Budapest