ATP‐sensitive K+ channels and cellular K+ loss in hypoxic and ischaemic mammalian ventricle.

Weiss, James N.; Venkatesh, Nagammal; Lamp, Scott T.

doi:10.1113/jphysiol.1992.sp019022

Cited by 178 publications

(150 citation statements)

References 50 publications

(99 reference statements)

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“…Our results are consistent with such a suggestion. During myocardial ischaemia, ADP i rises (Weiss et al, 1992) and we show that glimepiride becomes a less e ective blocker of sarcolemmal K ATP channels under such conditions.…”

Section: Possible Therapeutic Significancementioning

confidence: 73%

Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K_ATP channels

Lawrence

Rainbow

Davies

et al. 2002

British J Pharmacology

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1 We have investigated the e ects of the sulphonylurea, glimepiride, currently used to treat type 2 diabetes, on ATP-sensitive K + (K ATP ) currents of rat cardiac myocytes and on their cloned constituents Kir6.2 and SUR2A expressed in HEK 293 cells. 2 Glimepiride blocked pinacidil-activated whole-cell K ATP currents of cardiac myocytes with an IC 50 of 6.8 nM, comparable to the potency of glibenclamide in these cells. Glimepiride blocked K ATP channels formed by co-expression of Kir6.2/SUR2A subunits in HEK 293 cells in outside-out excised patches with a similar IC 50 of 6.2 nM. 3 Glimepiride was much less e ective at blocking K ATP currents activated by either metabolic inhibition (MI) with CN 7 and iodoacetate or by the K ATP channel opener diazoxide in the presence of inhibitors of F 0 /F 1 -ATPase (oligomycin) and creatine kinase (DNFB). Thus 10 mM glimepiride blocked pinacidil-activated currents by 499%, MI-activated currents by 70% and diazoxideactivated currents by 82%. 4 In inside-out patches from HEK 293 cells expressing the cloned K ATP channel subunits Kir6.2/ SUR2A, increasing the concentration of ADP (1 ± 100 mM), in the presence of 100 nM glimepiride, lead to signi®cant increases in Kir6.2/SUR2A channel activity. However, over the range tested, ADP did not a ect cloned K ATP channel activity in the presence of 100 nM glibenclamide. These results are consistent with the suggestion that ADP reduces glimepiride block of K ATP channels. 5 Our results show that glimepiride is a potent blocker of native cardiac K ATP channels activated by pinacidil and blocks cloned Kir6.2/SUR2A channels activated by ATP depletion with similar potency. However, glimepiride is much less e ective when K ATP channels are activated by MI and this may re¯ect a reduction in glimepiride block by increased intracellular ADP.

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Section: Possible Therapeutic Significancementioning

confidence: 73%

Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K_ATP channels

Lawrence

Rainbow

Davies

et al. 2002

British J Pharmacology

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“…We considered the hypothesis that the magnitude of human population growth might explain a large fraction of the recent acceleration of new adaptive alleles. To test this hypothesis, we constructed a model of historic and prehistoric population growth, based on historical and archaeological estimates of population size (1,38,39).…”

Section: Resultsmentioning

confidence: 99%

Recent acceleration of human adaptive evolution

Hawks

Wang²,

Cochran

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

391

267

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Genomic surveys in humans identify a large amount of recent positive selection. Using the 3.9-million HapMap SNP dataset, we found that selection has accelerated greatly during the last 40,000 years. We tested the null hypothesis that the observed age distribution of recent positively selected linkage blocks is consistent with a constant rate of adaptive substitution during human evolution. We show that a constant rate high enough to explain the number of recently selected variants would predict (i) site heterozygosity at least 10-fold lower than is observed in humans, (ii) a strong relationship of heterozygosity and local recombination rate, which is not observed in humans, (iii) an implausibly high number of adaptive substitutions between humans and chimpanzees, and (iv) nearly 100 times the observed number of highfrequency linkage disequilibrium blocks. Larger populations generate more new selected mutations, and we show the consistency of the observed data with the historical pattern of human population growth. We consider human demographic growth to be linked with past changes in human cultures and ecologies. Both processes have contributed to the extraordinarily rapid recent genetic evolution of our species.HapMap ͉ linkage disequilibrium ͉ Neolithic ͉ positive selection H uman populations have increased vastly in numbers during the past 50,000 years or more (1). In theory, more people means more new adaptive mutations (2). Hence, human population growth should have increased in the rate of adaptive substitutions: an acceleration of new positively selected alleles.Can this idea really describe recent human evolution? There are several possible problems. Only a small fraction of all mutations are advantageous; most are neutral or deleterious. Moreover, as a population becomes more and more adapted to its current environment, new mutations should be less and less likely to increase fitness. Because species with large population sizes reach an adaptive peak, their rate of adaptive evolution over geologic time should not greatly exceed that of rare species (3).But humans are in an exceptional demographic and ecological transient. Rapid population growth has been coupled with vast changes in cultures and ecology during the Late Pleistocene and Holocene, creating new opportunities for adaptation. The past 10,000 years have seen rapid skeletal and dental evolution in human populations and the appearance of many new genetic responses to diets and disease (4).In such a transient, large population, size increases the rate and effectiveness of adaptive responses. For example, natural insect populations often produce effective monogenic resistance to pesticides, whereas small laboratory populations under similar selection develop less effective polygenic adaptations (5). Chemostat experiments on Escherichia coli show a continued response to selection (6), with continuous and repeatable responses in large populations but variable and episodic responses in small populations (7). These results are explained by a model in...

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“…Elevated levels of intracellular MgADP, as it occurs under metabolic stress [15,[52][53][54][55] effectively decelerate ATPase cycling increasing the probability of the post-hydrolytic conformation associated with channel opening [9,14]. In this way, nucleotide exchange between the SUR ATPase and intracellular metabolic pathways could couple K ATP channel function with cellular energetics.…”

Section: Sur Catalysis-mediated Kir62 Channel Gatingmentioning

confidence: 99%

ATP-sensitive K channel channel/enzyme multimer: Metabolic gating in the heart

Alekseev

Hodgson

Karger

et al. 2005

Journal of Molecular and Cellular Cardiology

108

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Cardiac ATP-sensitive K + (K ATP ) channels, gated by cellular metabolism, are formed by association of the inwardly rectifying potassium channel Kir6.2, the potassium conducting subunit, and SUR2A, the ATP-binding cassette protein that serves as the regulatory subunit. Kir6.2 is the principal site of ATP-induced channel inhibition, while SUR2A regulates K + flux through adenine nucleotide binding and catalysis. The ATPase-driven conformations within the regulatory SUR2A subunit of the K ATP channel complex have determinate linkage with the states of the channel's pore. The probability and life-time of ATPase-induced SUR2A intermediates, rather than competitive nucleotide binding alone, defines nucleotide-dependent K ATP channel gating. Cooperative interaction, instead of independent contribution of individual nucleotide binding domains within the SUR2A subunit, serves a decisive role in defining K ATP channel behavior. Integration of K ATP channels with the cellular energetic network renders these channel/enzyme heteromultimers high-fidelity metabolic sensors. This vital function is facilitated through phosphotransfer enzyme-mediated transmission of controllable energetic signals. By virtue of coupling with cellular energetic networks and the ability to decode metabolic signals, K ATP channels set membrane excitability to match demand for homeostatic maintenance. This new paradigm in the operation of an ion channel multimer is essential in providing the basis for K ATP channel function in the cardiac cell, and for understanding genetic defects associated with life-threatening diseases that result from the inability of the channel complex to optimally fulfill its physiological role.

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ATP‐sensitive K+ channels and cellular K+ loss in hypoxic and ischaemic mammalian ventricle.

Cited by 178 publications

References 50 publications

Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K_ATP channels

Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K_ATP channels

Recent acceleration of human adaptive evolution

ATP-sensitive K channel channel/enzyme multimer: Metabolic gating in the heart

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ATP‐sensitive K+ channels and cellular K+ loss in hypoxic and ischaemic mammalian ventricle.

Cited by 178 publications

References 50 publications

Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal KATP channels

Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal KATP channels

Recent acceleration of human adaptive evolution

ATP-sensitive K channel channel/enzyme multimer: Metabolic gating in the heart

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Product

Resources

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Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K_ATP channels

Effect of metabolic inhibition on glimepiride block of native and cloned cardiac sarcolemmal K_ATP channels