ABCC7 p.Arg975Ala
| Predicted by SNAP2: | A: D (91%), C: D (80%), D: D (95%), E: D (95%), F: D (91%), G: D (95%), H: D (91%), I: D (85%), K: D (91%), L: D (91%), M: D (85%), N: D (95%), P: D (95%), Q: D (91%), S: D (91%), T: D (91%), V: D (91%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] CFTR inhibition by glibenclamide requires a positi... Biochim Biophys Acta. 2007 Oct;1768(10):2438-46. Epub 2007 May 21. Melin P, Hosy E, Vivaudou M, Becq F
CFTR inhibition by glibenclamide requires a positive charge in cytoplasmic loop three.
Biochim Biophys Acta. 2007 Oct;1768(10):2438-46. Epub 2007 May 21., [PMID:17582383]
Abstract [show]
The sulfonylurea glibenclamide is widely used as an open-channel blocker of the CFTR chloride channel. Here, we used site-directed mutagenesis to identify glibenclamide site of interaction: a positively charged residue K978, located in the cytoplasmic loop 3. Charge-neutralizing mutations K978A, K978Q, K978S abolished the inhibition of forskolin-activated CFTR chloride current by glibenclamide but not by CFTR(inh)-172. The charge-conservative mutation K978R did not alter glibenclamide sensitivity of CFTR current. Mutations of the neighbouring R975 (R975A, R975S, R975Q) did not affect electrophysiological and pharmacological properties of CFTR. No alteration of halide selectivity was observed with any of these CFTR mutant channels. This study identifies a novel potential inhibitor site within the CFTR molecule, and suggests a novel role of cytoplasmic loop three, within the second transmembrane domain of CFTR protein. This work is the first to report on the role of a residue in a cytoplasmic loop in the mechanism of action of the channel blocker glibenclamide.
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No. Sentence Comment
4 Mutations of the neighbouring R975 (R975A, R975S, R975Q) did not affect electrophysiological and pharmacological properties of CFTR.
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ABCC7 p.Arg975Ala 17582383:4:36
status: NEW114 After expression in HEK-293 cells, the whole-cell chloride currents recorded with charge neutralizing mutants CFTR-R975A, R975Q and R975S (Fig. 5) showed similar electrophysiological properties as CFTR-wt: linear activation with Fsk, inhibition by glibenclamide and by CFTRinh-172.
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ABCC7 p.Arg975Ala 17582383:114:115
status: NEW151 Original currents recorded on HEK-293 transfected with EGFP-CFTR-R975A with Fsk 10 bc; M (A), Fsk+Glib 100 bc;M (B), and Fsk+CFTRinh-172 10 bc;M (C).
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ABCC7 p.Arg975Ala 17582383:151:65
status: NEW152 (D) Representative time course of current densities from the charge neutralizing mutant EGFP-CFTR-R975A in presence of Fsk 10 bc;M, Fsk+Glib 100 bc;M, Fsk+CFTRinh-172 10 bc;M.
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ABCC7 p.Arg975Ala 17582383:152:98
status: NEW153 (E) Current-voltage relationships normalized by cell capacitance recorded from R975A (n=11), R975S (n=7) and R975Q (n=4) EGFP-CFTR channels in presence of agonists.
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ABCC7 p.Arg975Ala 17582383:153:79
status: NEW