α1-Adrenoreceptors regulate only the caveolae-located subpopulation of cardiac K<sub>V</sub>4 channels

Alday, Aintzane; Urrutia, Janire; Gallego, Mónica; Casis, Óscar

doi:10.4161/chan.4.3.11479

Cited by 18 publications

(21 citation statements)

References 29 publications

(41 reference statements)

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“…However, a population of these channels have been shown to be localised to caveolae-containing membrane fractions [39, 47], to interact with Cav3 (Balijepalli et al ., 2006), and to cluster with Cav3 in plasma membrane sheets [47] (see review by Best & Kamp in this issue). Other channels which have been linked with cAMP-dependent pathways, including the Na + channel and Kv4.2/4.3, are also present in both caveolar and non-caveolar fractions of the adult myocyte [38, 40, 47]. By contrast, the HCN4 channel is found exclusively in caveolar fractions of the adult sino-atrial node where it co-immunoprecipitates with Cav3 [48, 49].…”

Section: Caveolae As Signalling Protein Platformsmentioning

confidence: 99%

“…Regarding the former, α1-AR attenuation of the transient outward current ( I to ) via Gαs stimulation of a PKA-dependent pathway has been described [69], although the mechanism for α1-AR regulation of I to is controversial [70] and α1-AR stimulation has been shown to inhibit I Ca,L by reducing cAMP-dependent signalling [71]. α1-AR are found predominantly in caveolar fractions of the adult myocardium [40, 42] and it has recently been proposed that caveolae represent an α1-AR- I to regulatory domain in the adult ventricular myocyte, based on findings of 2 caveolar-based complexes, one of PKA tethered to the K V 4.2/K V 4.3 channel via AKAP100 and another containing α1-AR, Gαs and AC. These workers suggest that the population of I to channels present in Cav3-containing membrane domains is rapidly and specifically regulated by α1-AR stimulation of PKA; channels outside caveolae are still accessible to α1-AR signalling, but regulation is less efficient [40].…”

Section: Caveolae As Signalling Protein Platformsmentioning

confidence: 99%

“…α1-AR are found predominantly in caveolar fractions of the adult myocardium [40, 42] and it has recently been proposed that caveolae represent an α1-AR- I to regulatory domain in the adult ventricular myocyte, based on findings of 2 caveolar-based complexes, one of PKA tethered to the K V 4.2/K V 4.3 channel via AKAP100 and another containing α1-AR, Gαs and AC. These workers suggest that the population of I to channels present in Cav3-containing membrane domains is rapidly and specifically regulated by α1-AR stimulation of PKA; channels outside caveolae are still accessible to α1-AR signalling, but regulation is less efficient [40]. …”

Section: Caveolae As Signalling Protein Platformsmentioning

confidence: 99%

“…More recently, these findings have been extended to the cardiac cell. The α1-AR is found in caveolar fractions of the adult myocardium, along with its main transducing G protein, Gq [40, 42]. Whilst Gs/Gi-linked signalling relies on the protein constituents of caveolae, evidence suggests that Gq coupled cascades utilise specific changes in the lipid components of caveolae to create local signal domains.…”

Section: Caveolae As Lipid-dependent Signalling Compartmentsmentioning

confidence: 99%

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Caveolae create local signalling domains through their distinct protein content, lipid profile and morphology

Harvey¹,

Calaghan²

2012

Journal of Molecular and Cellular Cardiology

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Compartmentation of signalling allows multiple stimuli to achieve diverse cellular responses with only a limited pool of second messengers. This spatial control of signalling is achieved, in part, by cellular structures which bring together elements of a particular cascade. One such structure is the caveola, a flask-shaped lipid raft. Caveolae are well-recognised as signalosomes, platforms for assembly of signalling complexes of receptors, effectors and their targets, which can facilitate efficient and specific cellular responses. Here we extend this simple model and present evidence to show how the protein and lipid profiles of caveolae, as well as their characteristic morphology, define their roles in creating local signalling domains in the cardiac myocyte.

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Section: Caveolae As Signalling Protein Platformsmentioning

confidence: 99%

Section: Caveolae As Signalling Protein Platformsmentioning

confidence: 99%

Section: Caveolae As Signalling Protein Platformsmentioning

confidence: 99%

Section: Caveolae As Lipid-dependent Signalling Compartmentsmentioning

confidence: 99%

See 2 more Smart Citations

Caveolae create local signalling domains through their distinct protein content, lipid profile and morphology

Harvey¹,

Calaghan²

2012

Journal of Molecular and Cellular Cardiology

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“…During sympathetic stimulation noradrenaline reduces I to current amplitude in ventricular myocytes. This is an acute response mediated by the α1-adrenoceptors and involves activation of the Gαs-PKA pathway [9,10,11]. …”

Section: Introductionmentioning

confidence: 99%

Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the I_toCurrent Density in Type 1 Diabetic Rat Cardiomyocytes

Setién

Alday²,

Diaz-Asensio³

et al. 2013

Cell Physiol Biochem

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Background/Aims: In diabetic ventricular myocytes, transient outward potassium current (I_to) amplitude is severely reduced because of the impaired catecholamine release that characterizes diabetic autonomic neuropathy. Sympathetic nervous system exhibits a trophic effect on I_to since incubation of myocytes with noradrenaline restores current amplitude via beta-adrenoceptor (βAR) stimulation. Here, we investigate the intracellular signalling pathway though which incubation of diabetic cardiomyocytes with the βAR agonist isoproterenol recovers I_to amplitude to normal values. Methods: Experiments were performed in ventricular myocytes isolated from streptozotocin-diabetic rats. I_to current was recorded by using the patch-clamp technique. Kv4 channel expression was determined by immunofluorescence. Protein-protein interaction was determined by coimmunoprecipitation. Results: Stimulation of βAR activates first a Gαs protein, adenylyl cyclase and Protein Kinase A. PKA-phosphorylated receptor then switches to the Gαi protein. This leads to the activation of the βAR-Kinase-1 and further receptor phosphorylation and arrestin dependent internalization. The internalized receptor-arrestin complex recruits and activates cSrc and the MAPK cascade, where Ras, c-Raf1 and finally ERK1/2 mediate the increase in Kv4.2 and Kv4.3 protein abundance in the plasma membrane. Conclusion: β₂AR stimulation activates a Gαs and Gαi protein dependent pathway where the ERK1/2 modulates the Ito current amplitude and the density of the Kv4.2 and Kv4.2 channels in the plasma membrane upon sympathetic stimulation in diabetic heart.

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Electrophysiology and metabolism of caveolin-3-overexpressing mice

et al. 2016

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Caveolin-3 (Cav-3) plays a critical role in organizing signaling molecules and ion channels involved in cardiac conduction and metabolism. Mutations in Cav-3 are implicated in cardiac conduction abnormalities and myopathies. Additionally, cardiac specific overexpression of Cav-3 (Cav-3 OE) is protective against ischemic and hypertensive injury suggesting a potential role for Cav-3 in basal cardiac electrophysiology and metabolism involved in stress adaptation. We hypothesized that overexpression of Cav-3 may alter baseline cardiac conduction and metabolism. We examined: 1) ECG telemetry recordings at baseline and during pharmacological interventions, 2) ion channels involved in cardiac conduction with immunoblotting and computational modeling, and 3) baseline metabolism in Cav-3 OE and transgene negative littermate control mice. Cav-3 OE mice had decreased heart rates, prolonged PR intervals, and shortened QTc intervals with no difference in activity compared to control mice. Dobutamine or propranolol did not cause significant changes between experimental groups in maximal (dobutamine) or minimal (propranolol) heart rate. Cav-3 OE mice had an overall lower chronotropic response to atropine. Expression of Kv1.4 and Kv4.3 channels, Nav1.5 channels and connexin 43 were increased in Cav-3 OE mice. A computational model integrating the immunoblotting results indicated shortened action potential duration in Cav-3 OE mice linking the change in channel expression to the observed electrophysiology phenotype. Metabolic profiling showed no gross differences in VO2, VCO2, respiratory exchange ratio, and heat generation, feeding or drinking. In conclusion, Cav-3 OE mice have changes in ECG intervals, heart rates, and cardiac ion channel expression. These findings give novel mechanistic insights into previously reported Cav-3 dependent cardioprotection.

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α1-Adrenoreceptors regulate only the caveolae-located subpopulation of cardiac K_V4 channels

Cited by 18 publications

References 29 publications

Caveolae create local signalling domains through their distinct protein content, lipid profile and morphology

Caveolae create local signalling domains through their distinct protein content, lipid profile and morphology

Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the I_toCurrent Density in Type 1 Diabetic Rat Cardiomyocytes

Electrophysiology and metabolism of caveolin-3-overexpressing mice

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α1-Adrenoreceptors regulate only the caveolae-located subpopulation of cardiac KV4 channels

Cited by 18 publications

References 29 publications

Caveolae create local signalling domains through their distinct protein content, lipid profile and morphology

Caveolae create local signalling domains through their distinct protein content, lipid profile and morphology

Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the ItoCurrent Density in Type 1 Diabetic Rat Cardiomyocytes

Electrophysiology and metabolism of caveolin-3-overexpressing mice

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α1-Adrenoreceptors regulate only the caveolae-located subpopulation of cardiac K_V4 channels

Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the I_toCurrent Density in Type 1 Diabetic Rat Cardiomyocytes