ABCMdb

ABCC7 p.Lys978Ala

ClinVar:	c.2932A>T , p.Lys978* D , Likely pathogenic
Predicted by SNAP2:	A: D (71%), C: D (75%), D: D (91%), E: D (85%), F: D (85%), G: D (80%), H: D (71%), I: D (75%), L: D (80%), M: D (63%), N: D (71%), P: D (91%), Q: D (75%), R: D (66%), S: D (66%), T: D (75%), V: D (80%), W: D (91%), Y: D (80%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: N, F: D, G: D, H: D, I: D, L: D, M: D, N: N, P: D, Q: N, R: N, S: N, T: D, V: D, W: D, Y: D,

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Publications
[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
2 Charge-neutralizing mutations K978A, K978Q, K978S abolished the inhibition of forskolin-activated CFTR chloride current by glibenclamide but not by CFTRinh-172. Login to comment
77 We investigated the role of the charged residue K978 in the sequence ILNRFSKD of CL3 (Fig. 1B) described as a region physically close to the pore [29] and examined the interaction of glibenclamide with mutated EGFP-CFTR channels: K978A, K978Q, K978R, Fig. 2. Login to comment
84 Similar effects in the presence of Fsk were recorded with cells expressing K978A, K978Q, K978R and K978S mutants CFTR. Login to comment
96 To investigate the role of the charge of the side chain of K978 in glibenclamide resistance, different amino acid substitutions were examined: K978A, K978Q, K978R. Login to comment
98 Fig. 4A presents the ratio Iglib/Ifsk, recorded at -100 mV, with 100 bc;M glibenclamide, for K978A, K978Q, K978R, K978S channels compared to CFTR-wt. Login to comment
108 neutralizing mutations (K978A, K978Q) rendered channels insensitive to inhibition by glibenclamide as demonstrated by the time course of current recorded at +40 mV (Fig. 4B). Login to comment
128 (B) Examples of time course of current densities (between +40 mVand -40 mV) from the charge neutralizing mutants CFTR-K978Q (a0;) and CFTR-K978A (ef;) in presence of Fsk 10 bc;M, and Fsk+Glib 100 bc;M, and Fsk+CFTRinh-172 10 bc;M. Login to comment
138 This was the case for the mutations that neutralized the charge of the side chain of the residue 978 (K978A, K978Q, K978S). Login to comment