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001-es BibID:	BIBFORM123944
035-os BibID:	(scopus)85202905797 (wos)001293277100001
Első szerző:	Cs. Szabó Bence
Cím:	Novel insights into the modulation of the voltage-gated potassium channel KV1.3 activation gating by membrane ceramides / Cs. Szabo Bence, Szabo Mate, Nagy Peter, Varga Zoltan, Panyi Gyorgy, Kovacs Tamas, Zakany Florina
Dátum:	2024
ISSN:	0022-2275
Megjegyzések:	Membrane lipids extensively modulate the activation gating of voltage-gated potassium channels (KV), however, much less is known about the mechanisms of ceramide and glucosylceramide actions including which structural element is the main intramolecular target and whether there is any contribution of indirect, membrane biophysics-related mechanisms to their actions. We used two-electrode voltage-clamp fluorometry capable of recording currents and fluorescence signals to simultaneously monitor movements of the pore domain (PD) and the voltage sensor domain (VSD) of the KV1.3 ion channel after attaching an MTS-TAMRA fluorophore to a cysteine introduced into the extracellular S3-S4 loop of the VSD. We observed rightward shifts in the conductance-voltage (G-V) relationship, slower current activation kinetics, and reduced current amplitudes in response to loading the membrane with C16-ceramide (Cer) or C16-glucosylceramide (GlcCer). When analyzing VSD movements, only Cer induced a rightward shift in the fluorescence signal-voltage (F-V) relationship and slowed fluorescence activation kinetics, whereas GlcCer exerted no such effects. These results point at a distinctive mechanism of action with Cer primarily targeting the VSD, while GlcCer only the PD of KV1.3. Using environment-sensitive probes and fluorescence-based approaches, we show that Cer and GlcCer similarly increase molecular order in the inner, hydrophobic regions of bilayers, however, Cer induces a robust molecular reorganization at the membrane-water interface. We propose that this unique ordering effect in the outermost membrane layer in which the main VSD rearrangement involving an outward sliding of the top of S4 occurs can explain the VSD targeting mechanism of Cer, which is unavailable for GlcCer.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk ceramides glycolipids fluorescence microscopy lipids physical biochemistry two-electrode voltage-clamp fluorometry membrane biophysics ion channels KV1.3 lipid-protein interactions
Megjelenés:	Journal Of Lipid Research. - 65 : 8 (2024), p. 1-17.-
További szerzők:	Szabó Máté (1996-) (általános orvos) Nagy Péter (1971-) (biofizikus) Varga Zoltán (1969-) (biofizikus, szakfordító) Panyi György (1966-) (biofizikus) Kovács Tamás (1985-) (általános orvos) Zákány Florina (1989-) (általános orvos)
Pályázati támogatás:	FK146740 OTKA FK143400 OTKA K138075 OTKA ANN133421 OTKA K132906 OTKA K143071 OTKA ÚNKP-23-4-II-DE-169 Egyéb ÚNKP-23-5-DE-488 Egyéb ÚNKP-23-3-II-DE-426 Egyéb Bolyai János kutatási ösztöndíj BO/00392/23 MTA Bolyai János kutatási ösztöndíj BO/00676/24 MTA
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