Találati lista | Tudóstér

001-es BibID:	BIBFORM119089
Első szerző:	Tóth István Balázs (élettanász)
Cím:	Direct modulation of TRPM8 ion channels by rapamycin and analog macrolide immunosuppressants / Balázs István Tóth, Bahar Bazeli, Annelies Janssens, Erika Lisztes, Márk Racskó, Balázs Kelemen, Mihály Herczeg, Tamás Milán Nagy, Katalin E. Kövér, Argha Mitra, Attila Borics, Tamás Bíró, Thomas Voets
Dátum:	2024
ISSN:	2050-084X
Megjegyzések:	Rapamycin (sirolimus), a macrolide compound isolated from the bacterium Streptomyces hygroscopicus, is widely used as oral medication for the prevention of transplant rejection and the treatment of lymphangioleiomyomatosis. It is also incorporated in coronary stent coatings to prevent restenosis and in topical preparations for the treatment of skin disorders. Rapamycin's in vivo activities are generally ascribed to its binding to the protein FKBP12, leading to potent inhibition of the mechanistic target of rapamycin kinase (mTOR) by the FKBP12-rapamycin complex. The specific rapamycin-induced interaction between domains from mTOR and FKBP12 is also frequently employed in cell biological research, for rapid chemically-induced protein dimerization strategies. Here we show that rapamycin activates TRPM8, a cation channel expressed in sensory nerve endings that serves as the primary cold sensor in mammals. Using a combination of electrophysiology, Saturation Transfer Triple-Difference (STTD) NMR spectroscopy and molecular docking-based targeted mutagenesis, we demonstrate that rapamycin directly binds to TRPM8. We identify a rapamycin-binding site in the groove between voltage sensor-like domain and the pore domain, distinct from the interaction sites of cooling agents and known TRPM8 agonists menthol and icilin. Related macrolide immunosuppressants act as partial TRPM8 agonists, competing with rapamycin for the same binding site. These findings identify a novel molecular target for rapamycin and provide new insights into the mechanisms of TRPM8 activation, which may assist in the development of therapies targeting this ion channel. Moreover, our findings also indicate that caution is needed when using molecular approaches based on rapamycin-induced dimerization to study ion channel regulation.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk TRPM8 Rapamycin Electrophysiology NMR spectroscopy Neuroscience
Megjelenés:	eLife. - "Accepted by Publisher" (2024). -
További szerzők:	Bazeli, Bahar Janssens, Annelies Lisztes Erika (1986-) (élettanász) Racskó Márk (1991-) (molekuláris biológus) Kelemen Balázs (1992-) (biológus) Herczeg Mihály (1979-) (vegyész, biológia-kémia tanár) Nagy Tamás Milán (1993-) (vegyész, nmr) Kövér Katalin, E. (1956-2023) (vegyész) Mitra, Argha Borics Attila Bíró Tamás (1968-) (élettanász) Voets, Thomas
Pályázati támogatás:	134725 OTKA 134791 OTKA 128368 OTKA 137924 OTKA GINOP-2.3.2-15-2016-00050 GINOP GINOP-2.3.3-15-2016-00004 GINOP GINOP-2.2.1-15-2017-00044 GINOP János Bolyai Research Scholarship Egyéb ÚNKP-22-3-I-DE-324 Egyéb ÚNKP-23-3-II-DE-430 Egyéb UNKP-22-4-I-DE-87 Egyéb ÚNKP-21-5-DE-491 Egyéb FWO; G0B9520N Egyéb FWO; G0B7620N Egyéb esearch Council of KU Leuven (C2-TRP) Egyéb Queen Elisabeth Medical Foundation for Neurosciences Egyéb EU's Horizon 2020 research and innovation program under grant agreement No. 739593 Egyéb
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat
Borító:
Saját polcon: