Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes

Girard, Christophe A.; Shimomura, Kenju; Proks, Peter; Absalom, Nathan L.; Castaño, Luís; Nanclares, Guiomar Perez de; Ashcroft, Frances M.

doi:10.1007/s00424-006-0112-3

Cited by 57 publications

(60 citation statements)

References 47 publications

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“…Although for the R301G, R301H, and R301P, channel expression defect is likely the predominant factor underlying loss of channel function, for the R301C mutation channel inactivation likely plays a significant role in causing ␤-cell defect. Curiously, Girard et al (38) recently reported identification of a Kir6.2 mutation E229K in transient neonatal diabetes. Glu-229 forms an intersubunit ion pair with Arg-314, and disruption of this ion pair with the E229R mutation induces rapid current decay or inactivation (20).…”

Section: Discussionmentioning

confidence: 99%

Destabilization of ATP-sensitive Potassium Channel Activity by Novel KCNJ11 Mutations Identified in Congenital Hyperinsulinism

Lin

Bushman

Yan

et al. 2008

Journal of Biological Chemistry

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The inwardly rectifying potassium channel Kir6.2 is the pore-forming subunit of the ATP-sensitive potassium (K ATP ) channel, which controls insulin secretion by coupling glucose metabolism to membrane potential in ␤-cells. Loss of channel function because of mutations in Kir6.2 or its associated regulatory subunit, sulfonylurea receptor 1, causes congenital hyperinsulinism (CHI), a neonatal disease characterized by persistent insulin secretion despite severe hypoglycemia. Here, we report a novel K ATP channel gating defect caused by CHI-associated Kir6.2 mutations at arginine 301 (to cysteine, glycine, histidine, or proline). These mutations in addition to reducing channel expression at the cell surface also cause rapid, spontaneous current decay, a gating defect we refer to as inactivation. Based on the crystal structures of Kir3.1 and KirBac1.1, Arg-301 interacts with several residues in the neighboring Kir6.2 subunit. Mutation of a subset of these residues also induces channel inactivation, suggesting that the disease mutations may cause inactivation by disrupting subunit-subunit interactions. To evaluate the effect of channel inactivation on ␤-cell function, we expressed an alternative inactivation mutant R301A, which has equivalent surface expression efficiency as wild type channels, in the insulin-secreting cell line INS-1. Mutant expression resulted in more depolarized membrane potential and elevated insulin secretion at basal glucose concentration (3 mM) compared with cells expressing wild type channels, demonstrating that the inactivation gating defect itself is sufficient to cause loss of channel function and hyperinsulinism. Our studies suggest the importance of Kir6.2 subunit-subunit interactions in K ATP channel gating and function and reveal a novel gating defect underlying CHI.Inwardly rectifying potassium (Kir) channels are important for governing the resting membrane potential in a wide variety of cell types (1). In the islet ␤-cell, Kir6.2 complexes with the sulfonylurea receptor 1 (SUR1) 2 to form the ATP-sensitive potassium (K ATP ) channel which regulates membrane potential according to the energetic state of the cell, thereby mediating glucose-stimulated insulin secretion (2-4). The gating properties that are critical for the physiological function of K ATP channels are their sensitivity to intracellular nucleotides ATP and ADP, whose concentrations fluctuate as glucose levels vary. Both Kir6.2 and SUR1 subunits participate in nucleotide regulation of the channel; ATP inhibits channel activity by binding to the Kir6.2 subunit, whereas Mg 2ϩ -complexed ATP and ADP stimulate channel activity by interacting with SUR1. As glucose concentrations rise, K ATP channels are driven to closure by the increase in ATP and decrease in ADP levels, resulting in membrane depolarization, activation of voltage-gated calcium channels, and insulin secretion. On the other hand, a fall in glucose concentrations promotes K ATP channel opening to stop insulin secretion. Other molecules that have emerged from recen...

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Section: Discussionmentioning

confidence: 99%

Destabilization of ATP-sensitive Potassium Channel Activity by Novel KCNJ11 Mutations Identified in Congenital Hyperinsulinism

Lin

Bushman

Yan

et al. 2008

Journal of Biological Chemistry

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“…Interestingly, this shift in ATP sensitivity appears to be much greater for mutant channels with gain-of function mutations in Kir6.2 than that of the wild-type channel (Fig. 6) [51][52][53][54][55][56]. Thus it seems that in addition to reduction of the inhibitory effect of ATP, gain-offunction mutations in Kir6.2 can also somehow enhance the activatory effect of Mg-nucleotides.…”

Section: Molecular Basis Of Reduced Atp Sensitivitymentioning

confidence: 96%

“…As a result, channels with gating mutations have increased Po values compared to that of the wild type channel (Fig. 5B) [51,52,54,56,57]. Because the affinity of ATP for the channel open state is smaller than for the closed state, channels are less inhibited by ATP in these mutations.…”

Section: Molecular Basis Of Reduced Atp Sensitivitymentioning

confidence: 97%

“…These mutations usually do not affect properties of channel gating in the absence of the nucleotide: the fraction of time that channel spends in the open state (open probability: Po) in ligand free solutions is similar to that of the wild-type channel (Fig. 5B), On the other hand, mutations which are located in regions which are predicted to be involved in channel gating affect ATP inhibition indirectly [51,52,[54][55][56][57]. These mutations shift channel gating towards the open state.…”

Section: Molecular Basis Of Reduced Atp Sensitivitymentioning

confidence: 98%

“…All neonatal diabetes mutations in K ATP channels are gain-of-function mutations [1,44,[51][52][53][54][55][56][57]. Although mutations in both Kir6.2 and SUR1 have been reported, this review is focused only on Kir6.2 mutations.…”

Section: Gain Of Function Mutations In Kir62 (Kcnj11)mentioning

confidence: 99%

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The KATP Channel and Neonatal Diabetes

Shimomura

2009

Endocr J

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Abstract. ATP-sensitive potassium (K ATP ) channels play a key role in glucose-dependent insulin secretion in pancreatic β-cells. Recently, activating mutations in β-cell K ATP channels were found to be an important cause of neonatal diabetes. In some patients, these mutations may also affect K ATP channel function in muscles, nerves and brain which can result in a severe disease termed DEND syndrome (Developmental delay, Epilepsy and Neonatal Diabetes). This review focuses on mutations in the pore-forming K ATP channel subunit (Kir6.2) that cause neonatal diabetes and discusses recent advances in our understanding of clinical features of neonatal diabetes, its underlying molecular mechanisms and their impact on treatment.

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ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

Tinker

Aziz

et al. 2018

Comprehensive Physiology

111

112

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ATP sensitive potassium channels (K ) are so named because they open as cellular ATP levels fall. This leads to membrane hyperpolarization and thus links cellular metabolism to membrane excitability. They also respond to MgADP and are regulated by a number of cell signaling pathways. They have a rich and diverse pharmacology with a number of agents acting as specific inhibitors and activators. K channels are formed of pore-forming subunits, Kir6.1 and Kir6.2, and a large auxiliary subunit, the sulfonylurea receptor (SUR1, SUR2A, and SUR2B). The Kir6.0 subunits are a member of the inwardly rectifying family of potassium channels and the sulfonylurea receptor is part of the ATP-binding cassette family of proteins. Four SURs and four Kir6.x form an octameric channel complex and the association of a particular SUR with a specific Kir6.x subunit constitutes the K current in a particular tissue. A combination of mutagenesis work combined with structural studies has identified how these channels work as molecular machines. They have a variety of physiological roles including controlling the release of insulin from pancreatic β cells and regulating blood vessel tone and blood pressure. Furthermore, mutations in the genes underlie human diseases such as congenital diabetes and hyperinsulinism. Additionally, opening of these channels is protective in a number of pathological conditions such as myocardial ischemia and stroke. © 2018 American Physiological Society. Compr Physiol 8:1463-1511, 2018.

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Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes

Cited by 57 publications

References 47 publications

Destabilization of ATP-sensitive Potassium Channel Activity by Novel KCNJ11 Mutations Identified in Congenital Hyperinsulinism

Destabilization of ATP-sensitive Potassium Channel Activity by Novel KCNJ11 Mutations Identified in Congenital Hyperinsulinism

The KATP Channel and Neonatal Diabetes

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

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