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001-es BibID:	BIBFORM105306
035-os BibID:	(WoS)000883005300001 (Scopus)85141634111
Első szerző:	Wai, Dorothy C. C.
Cím:	A Fluorescent Peptide Toxin for Selective Visualization of the Voltage-Gated Potassium Channel Kv1.3 / Wai Dorothy C. C., Naseem Muhammad Umair, Mocsár Gábor, Babu Reddiar Sanjeevini, Pan Yijun, Csoti Agota, Hajdu Peter, Nowell Cameron, Nicolazzo Joseph A., Panyi Gyorgy, Norton Raymond S.
Dátum:	2022
ISSN:	1043-1802
Megjegyzések:	Upregulation of the voltage-gated potassium channel K(V)1.3 is implicated in a range of autoimmune and neuroinflammatory diseases, including rheumatoid arthritis, psoriasis, multiple sclerosis, and type I diabetes. Understanding the expression, localization, and trafficking of K(V)1.3 in normal and disease states is key to developing targeted immunomodulatory therapies. HsTX1[R14A], an analogue of a 34-residue peptide toxin from the scorpion Heterometrus spinifer, binds K(V)1.3 with high affinity (IC50 of 45 pM) and selectivity (2000-fold for K(V)1.3 over K(V)1.1). We have synthesized a fluorescent analogue of HsTX1[R14A] by N-terminal conjugation of a Cy5 tag. Electrophysiology assays show that Cy5-HsTX1[R14A] retains activity against K(V)1.3 (IC50 similar to 0.9 nM) and selectivity over a range of other potassium channels (K(V)1.2, K(V)1.4, K(V)1.5, K(V)1.6, K(Ca)1.1 and K(Ca)3.1), as well as selectivity against heteromeric channels assembled from K(V)1.3/K(V)1.5 tandem dimers. Live imaging of CHO cells expressing green fluorescent protein-tagged K(V)1.3 shows co-localization of Cy5-HsTX1[R14A] and K(V)1.3 fluorescence signals at the cell membrane. Moreover, flow cytometry demonstrated that Cy5-HsTX1[R14A] can detect K(V)1.3-expressing CHO cells. Stimulation of mouse microglia by lipopolysaccharide, which enhances membrane expression of K(V)1.3, was associated with increased staining by Cy5-HsTX1[R14A], demonstrating that it can be used to identify K(V)1.3 in disease-relevant models of inflammation. Furthermore, the biodistribution of Cy5-HsTX1[R14A] could be monitored using ex vivo fluorescence imaging of organs in mice dosed subcutaneously with the peptide. These results illustrate the utility of Cy5-HsTX1[R14A] as a tool for visualizing K(V)1.3, with broad applicability in fundamental investigations of K(V)1.3 biology, and the validation of novel disease indications where K(V)1.3 inhibition may be of therapeutic value.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban folyóiratcikk Fluorescence Imaging probes Peptides and proteins Potassium Selectivity
Megjelenés:	Bioconjugate Chemistry. - 33 : 11 (2022), p. 2197-2212. -
További szerzők:	Naseem, Muhammad Umair (1993-) (biofizikus, molekuláris biológus) Mocsár Gábor (1981-) (biofizikus) Babu Reddiar, Sanjeevini Pan, Yijun Csóti Ágota (1989-) (biológus) Hajdu Péter (1975-) (biofizikus) Nowell, Cameron Nicolazzo, Joseph A. Panyi György (1966-) (biofizikus) Norton, Raymond S.
Pályázati támogatás:	K143071 OTKA K128525 OTKA EFOP-3.6.1-16-2016-00022 EFOP GINOP-2.3.2-15-2016-00015 GINOP Stipendium Hungaricum Scholarship by the Tempus Public Foundation Egyéb
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