Actin microfilament disrupters enhance K(ATP) channel opening in patches from guinea‐pig cardiomyocytes.

Terzic, André; Kurachi, Yoshihisa

doi:10.1113/jphysiol.1996.sp021316

Cited by 101 publications

(82 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For well over a decade, the ion channel field has struggled to identify the molecular link between the K ATP channel and the cytoskeleton (24)(25)(26). The presence of an adapter complex was first proposed in the mid 1990's, based on a series of experiments that demonstrated a striking stimulatory effect of actin filament disrupting agents on K ATP channel opening (25).…”

Section: Discussionmentioning

confidence: 99%

“…The presence of an adapter complex was first proposed in the mid 1990's, based on a series of experiments that demonstrated a striking stimulatory effect of actin filament disrupting agents on K ATP channel opening (25). Specifically, disruption of the actin cytoskeleton has been shown to activate K ATP channel activity in excitable cells by reducing the sensitivity of K ATP channels to ATP-dependent channel closure (24)(25)(26). Thus, impairment in ATP sensitivity indicates a transduction pathway of inhibitory gating signals determined by the integrity of the submembrane cytoskeletal network.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dual role of K _ATP channel C-terminal motif in membrane targeting and metabolic regulation

Kline

Kurata

Hund

et al. 2009

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

View full text Add to dashboard Cite

The coordinated sorting of ion channels to specific plasma membrane domains is necessary for excitable cell physiology. KATP channels, assembled from pore-forming (Kir6.x) and regulatory sulfonylurea receptor subunits, are critical electrical transducers of the metabolic state of excitable tissues, including skeletal and smooth muscle, heart, brain, kidney, and pancreas. Here we show that the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells. Kir6.2 lacking this motif displays aberrant channel targeting due to loss of association with the membrane adapter ankyrin-B (AnkB). Moreover, we demonstrate that this Kir6.2 C-terminal AnkB-binding motif (ABM) serves a dual role in KATP channel trafficking and membrane metabolic regulation and dysfunction in these pathways results in human excitable cell disease. Thus, the KATP channel ABM serves as a previously unrecognized bifunctional touch-point for grading KATP channel gating and membrane targeting and may play a fundamental role in controlling excitable cell metabolic regulation.K ATP channels are critical electrical transducers of the metabolic state of excitable tissues including skeletal and smooth muscle, heart, brain, kidney, and pancreas (1). Mechanistically, decreased metabolism opens K ATP channels, resulting in K ϩ efflux, membrane hyperpolarization, and suppression of action potential formation (1). Conversely, increased metabolism closes K ATP channels, resulting in membrane depolarization, stimulation of electrical activity (2), and subsequent triggering of diverse cellular responses, such as release of hormones and neurotransmitters, or muscle contraction.Given such critical roles in the regulation of electrical excitability in many cell types, it is not surprising that K ATP channel dysfunction results in disease. Human mutations in K ATP channel genes are associated with neonatal diabetes and hyperinsulinemia (3), epilepsy (4), and dilated cardiomyopathy (5). However, despite the clear importance of K ATP function for normal vertebrate physiology, little is resolved regarding the mechanisms responsible for K ATP channel membrane targeting and/or membrane organization.Here we identify a critical motif in the Kir6.2 C-terminal domain that is essential for normal Kir6.2 membrane targeting. We demonstrate that the Kir6.2 C-terminal motif interacts with the cytoskeletal adapter ankyrin-B (AnkB) and that Kir6.2 displays aberrant membrane trafficking when the motif is disrupted or in cells lacking ankyrin-B expression. We demonstrate that the Kir6.2 C-terminal motif displays an unexpected secondary role in Kir6.2 membrane function (K ATP channel activity) by altering K ATP channel ATP sensitivity. Finally, we demonstrate that a human neonatal diabetes disease mutation located in the Kir6.2 C-terminal motif results in a complex ␤ cell phenotype, likely due to the dual role of the C-terminal motif in both Kir6.2 targeting and K ATP channel membrane activity. Together, our findings define a pathway for K ATP ch...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dual role of K _ATP channel C-terminal motif in membrane targeting and metabolic regulation

Kline

Kurata

Hund

et al. 2009

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

View full text Add to dashboard Cite

show abstract

“…There are several contributors including physical interactions between the channel and the actin cytoskeleton [95][96][97][98][99], as well as additional metabolic systems such as lactate dehydrogenase (LDH) that, like CK and AK has also been shown to physical associate with K ATP channel proteins [8,91,100]. LDH catalyzes the reaction NADH + pyruvate ↔ lactate + NAD.…”

Section: The K Atp Channel Complex As a Component Of The Cellular Enementioning

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

Self Cite

108

View full text Add to dashboard Cite

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.

show abstract

“…Second, since the molecular identity of the insulin-responsive ion channels is not known, a direct effect of PI 3-kinase inhibitors or nocodazole on these channels that are already present in the plasma membrane cannot be completely excluded. This seems unlikely, since these inhibitors have no direct effect on ion channel activity in excised patches (46,47).…”

Section: Discussionmentioning

confidence: 99%

Insulin Stimulates Membrane Conductance in a Liver Cell Line

Kilic

Doctor

Fitz

2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

Activation of insulin receptors stimulates a rapid increase in the ion permeability of liver cells. To evaluate whether this response involves insertion of ion channels, plasma membrane turnover was measured in a model liver cell line using the fluorescent membrane marker FM1-43. Under basal conditions, the rate of constitutive membrane turnover was ϳ2%min ؊1 , and balanced exocytosis and endocytosis maintained the total cell membrane area constant. Exposure to insulin stimulated a transient increase in membrane turnover of up to 10-fold above constitutive rates. The response was concentration-dependent (0.001-10 M). Insulin also caused a parallel increase in membrane conductance as measured by whole-cell patch clamp recording due to opening of Cl ؊ -and K ؉ -selective ion channels. The insulin-stimulated membrane turnover did not appear to involve the constitutive recycling compartments, suggesting that a distinct pool of vesicles may be involved. The effects of insulin on membrane turnover and membrane conductance were inhibited by blockers of phosphoinositide 3-kinase LY294002 and wortmannin or by disrupting microtubule assembly with nocodazole. Taken together, these findings indicate that insulin stimulates recruitment of new membranes through phosphoinositide 3-kinase-dependent mechanisms. Thus, regulated insertion of a separate population of ion channel-containing vesicles may represent one mechanism for mediating the changes in membrane conductance that are essential for the cellular response to insulin.Liver cells exhibit rapid regulation of solute transport across the plasma membrane in response to changing physiological demands. Changes in the concentration of solutes in the extracellular space are followed by increased uptake of glucose, amino acids, and bile acids as well as an increase in the activity of specific enzymes that regulate glucose metabolism and bile formation. While many of the individual transport proteins involved have been molecularly defined, little is known regarding the cellular strategies for regulating the number, type, and activity of transporters in the plasma membrane under defined physiological conditions. In other cells, insertion or retrieval of transport proteins through vesicular exocytosis or endocytosis regulates the protein composition of the plasma membrane (1). In adipocytes, for example, insulin-stimulated glucose uptake is mediated by insertion of glucose transporter GLUT4-containing vesicles, leading to an increase in total transport capacity (2). These effects appear to be mediated in part by phosphoinositide 3-kinase (PI 3-kinase).1 This kinase phosphorylates phosphatidylinositols at the D3 position, and the resulting lipid-signaling molecules have been implicated in recruitment or activation of proteins essential for vesicular transport (3-6). In liver, insulin receptor binding leads to an increase in ion channel activity, and the resulting increases in membrane conductance appear to be an early and essential step necessary for subsequent changes in transport ...

show abstract

Actin microfilament disrupters enhance K(ATP) channel opening in patches from guinea‐pig cardiomyocytes.

Cited by 101 publications

References 37 publications

Dual role of K _ATP channel C-terminal motif in membrane targeting and metabolic regulation

Dual role of K _ATP channel C-terminal motif in membrane targeting and metabolic regulation

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

Insulin Stimulates Membrane Conductance in a Liver Cell Line

Contact Info

Product

Resources

About

Actin microfilament disrupters enhance K(ATP) channel opening in patches from guinea‐pig cardiomyocytes.

Cited by 101 publications

References 37 publications

Dual role of K ATP channel C-terminal motif in membrane targeting and metabolic regulation

Dual role of K ATP channel C-terminal motif in membrane targeting and metabolic regulation

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

Insulin Stimulates Membrane Conductance in a Liver Cell Line

Contact Info

Product

Resources

About

Dual role of K _ATP channel C-terminal motif in membrane targeting and metabolic regulation

Dual role of K _ATP channel C-terminal motif in membrane targeting and metabolic regulation