ArticleThe Journal of physiology2011
A conserved tryptophan at the membrane-water interface acts as a gatekeeper for Kir6.2/SUR1 channels and causes neonatal diabetes when mutated.
Article in The Journal of physiology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed, 21 citations in OpenAlex.
- Kir6.2 channel activity is regulated by interaction of transmembrane domains 1 and 2 through I167 in the bundle-crossing gate.Physiological reports · 2025Article
- Cooperative Gating of a KJournal of the American Chemical Society · 2024Article
- The dynamic interplay of PIPThe Journal of physiology · 2022Article
- Integrative Study of the Structural and Dynamical Properties of a KirBac3.1 Mutant: Functional Implication of a Highly Conserved Tryptophan in the Transmembrane Domain.International journal of molecular sciences · 2021Article
- Simulating PIPFrontiers in molecular biosciences · 2021Article
- New insights into KNature reviews. Endocrinology · 2020Review
- The value of in vitro studies in a case of neonatal diabetes with a novel Kir6.2-W68G mutation.Clinical case reports · 2015Article
- A Conserved Residue Cluster That Governs Kinetics of ATP-dependent Gating of Kir6.2 Potassium Channels.The Journal of biological chemistry · 2015Article
- Xenopus as a Model for GI/Pancreas Disease.Current pathobiology reports · 2015Article
- Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach.Molecular genetics and metabolism · 2014Article
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Authors and funding
7 authors at 3 institutions in 1 country.
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Abstract
We identified a novel heterozygous mutation, W68R, in the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, in a patient with transient neonatal diabetes. This tryptophan is absolutely conserved in mammalian Kir channels. The functional effects of mutations at residue 68 of Kir6.2 were studied by heterologous expression in Xenopus oocytes, and by homology modelling. We found the Kir6.2-W68R mutation causes a small reduction in ATP inhibition in the heterozygous state and an increase in the whole-cell KATP current. This can explain the clinical phenotype of the patient. The effect of the mutation was not charge or size dependent, the order of potency for ATP inhibition being W<M∼L<R∼E∼K∼A<C∼F<Y. Replacement with tyrosine (Y) rendered the KATP channel almost completely insensitive to ATP block, dramatically increased the channel open probability, and affected the interaction of Kir6.2 with SUR1. In different Kir crystal structures the residue corresponding to W68 adopts two distinct positions. In one state, the tryptophan lies in a position that would impede movement of transmembrane domain 2 (TM2) and opening of the gate. In the other state, it is flipped out, enabling movement of TM2. We therefore hypothesise that W68 may act as a molecular'gatekeeper' for Kir channels.
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