Author: Almássy, János ; Jeremic, Dusan ; Lengyel, Miklós ; Hoetzenecker, Konrad ; Csáki, Réka ; Khozeimeh, Mohammad Ali ; Dobolyi, Alice ; Enyedi, Péter ; Olschewski, Horst ; Olschewski, Andrea ; Nagaraj, Chandran

AbstractBackground and purposePulmonary arterial hypertension (PAH) is a progressive disease in which chronic membrane potential (Em) depolarisation of the pulmonary arterial smooth muscle cells (PASMCs) causes calcium overload, a key pathological alteration. Under resting conditions, the negative Em is mainly set by two pore domain potassium (K2P) channels, of which the TASK‐1 has been extensively investigated.Experimental ApproachIon channel currents and membrane potential of primary cultured human(h) PASMCs were measured using the voltage‐ and current clamp methods. Intracellular [Ca2+] was monitored using fluorescent microscopy. Pulmonary BP and vascular tone measurements were also performed ex vivo using a rat PAH model.Key ResultsTREK‐1 was the most abundantly expressed K2P in hPASMCs of healthy donors and idiopathic(I) PAH patients. Background K+‐current was similar in hPASMCs for both groups and significantly enhanced by the TREK activator ML‐335. In donor hPASMCs, siRNA silencing or pharmacological inhibition of TREK‐1 caused depolarisation, reminiscent of the electrophysiological phenotype of idiopathic PAH. ML‐335 hyperpolarised donor hPASMCs and normalised the Em of IPAH hPASMCs. A close link was found between TREK‐1 activity and intracellular Ca2+‐signalling using a channel activator, ML‐335, and an inhibitor, spadin. In the rat, ML‐335 relaxed isolated pre‐constricted pulmonary arteries and significantly decreased pulmonary arterial pressure in the isolated perfused lung.Conclusions and ImplicationsThese data suggest that TREK‐1is a key factor in Em setting and Ca2+ homeostasis of hPASMC, and therefore, essential for maintenance of a low resting pulmonary vascular tone. Thus TREK‐1 may represent a new therapeutic target for PAH.

01 Jul 2024·Cell Chemical Biology

Development of covalent chemogenetic K2P channel activators

Article

Author: Black, Holly ; Minor, Daniel L ; Lee, Haerim ; Lolicato, Marco ; Bryant, Clifford ; Mondal, Abhisek ; Deal, Parker E ; Isacoff, Ehud Y ; Jang, Seil ; Renslo, Adam R ; El-Hilali, Xochina ; Mendonça, Philipe Ribeiro Furtado de

K_2P potassium channels regulate excitability by affecting cellular resting membrane potential in the brain, cardiovascular system, immune cells, and sensory organs. Despite their important roles in anesthesia, arrhythmia, pain, hypertension, sleep, and migraine, the ability to control K_2P function remains limited. Here, we describe a chemogenetic strategy termed CATKLAMP (covalent activation of TREK family K⁺ channels to clamp membrane potential) that leverages the discovery of a K_2P modulator pocket site that reacts with electrophile-bearing derivatives of a TREK subfamily small-molecule activator, ML335, to activate the channel irreversibly. We show that CATKLAMP can be used to probe fundamental aspects of K_2P function, as a switch to silence neuronal firing, and is applicable to all TREK subfamily members. Together, our findings exemplify a means to alter K_2P channel activity that should facilitate molecular and systems level studies of K_2P function and enable the search for new K_2P modulators.

18 Oct 2023·bioRxiv : the preprint server for biology

Development of covalent chemogenetic K_2P channel activators.

Author: Mondal, Abhisek ; Minor, Daniel L ; Renslo, Adam R ; Deal, Parker E ; Bryant, Clifford ; de Mendonca, Philipe Ribeiro Furtado ; Black, Holly ; El-Hilali, Xochina ; Lolicato, Marco ; Isacoff, Ehud Y ; Lee, Haerim

K_2P potassium channels regulate excitability by affecting cellular resting membrane potential in the brain, cardiovascular system, immune cells, and sensory organs. Despite their important roles in anesthesia, arrhythmia, pain, hypertension, sleep, and migraine, the ability to control K_2P function remains limited. Here, we describe a chemogenetic strategy termed CATKLAMP (Covalent Activation of TREK family K⁺ channels to cLAmp Membrane Potential) that leverages the discovery of a site in the K_2P modulator pocket that reacts with electrophile-bearing derivatives of a TREK subfamily small molecule activator, ML335, to activate the channel irreversibly. We show that the CATKLAMP strategy can be used to probe fundamental aspects of K_2P function, as a switch to silence neuronal firing, and is applicable to all TREK subfamily members. Together, our findings exemplify a new means to alter K_2P channel activity that should facilitate studies both molecular and systems level studies of K_2P function and enable the search for new K_2P modulators.

100 Deals associated with ML-335

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Indication	Highest Phase	Country/Location	Organization	Date
Gout	Preclinical	China	North Sichuan Medical College	22 Aug 2024
Pain	Preclinical	Japan	Ono Pharmaceutical Co., Ltd.	10 Jul 2017
Pain	Preclinical	United States	University of California	10 Jul 2017

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