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

Harvey, Robert D.; Calaghan, Sarah

doi:10.1016/j.yjmcc.2011.07.007

Cited by 90 publications

(69 citation statements)

References 122 publications

(201 reference statements)

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“…Increased osmotic stress greatly changed the release of Ca 2ϩ with G␣ q /PLC␤ stimulation (12,29). In unstimulated A10 cells, we found that lowering the osmolarity does not affect the basal Ca 2ϩ levels and in contrast to previous reports showed that osmotic stress increases external Ca 2ϩ leakage (29), suggesting that leakage may be cell-specific.…”

Section: Discussioncontrasting

confidence: 66%

“…On the cellular level, caveolae are thought to play a role in endocytosis and trafficking (10), although this has been disputed (11). Caveolae can also serve as a platform to organize and corral signaling molecules such as the ones involved in nitric oxide production (8,12). Early studies of caveolae postulated that they can play a role in mechanosensing, and the high density of caveolae in cells that undergo mechanical stress supported this idea.…”

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confidence: 99%

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Osmotic Stress Reduces Ca2+ Signals through Deformation of Caveolae

Guo

Haught

et al. 2015

Journal of Biological Chemistry

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Background: Caveolae are membrane domains that have been shown to enhance G␣ q signals. Results: Osmotic stress deforms caveolae, reduces the association of G␣ q , and reduces G␣ q -mediated Ca 2ϩ release. Conclusion: Mechanical deformation of caveolae weakens Ca 2ϩ responses through changes in G␣ q interactions. Significance: These studies connect the mechanical and signaling functions of caveolae.

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Section: Discussioncontrasting

confidence: 66%

mentioning

confidence: 99%

Osmotic Stress Reduces Ca2+ Signals through Deformation of Caveolae

Guo

Haught

et al. 2015

Journal of Biological Chemistry

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“…The basis for this difference is unclear, with all studies using isolated perfused rodent hearts and similar ranges of M␤CD concentration. However, repression of contractile function is consistent with the significant influences of membrane cholesterol and caveolae on a variety of ion channels, receptor function and signaling, and other physiological processes (3,4,13,22).…”

Section: Discussionsupporting

confidence: 56%

Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection

Hoe

Schilling

Tarbit

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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See Hoe LE, Schilling JM, Tarbit E, Kiessling CJ, Busija AR, Niesman IR, Du Toit E, Ashton KJ, Roth DM, Headrick JP, Patel HH, Peart JN. Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection. Am J Physiol Heart Circ Physiol 307: H895-H903, 2014. First published July 25, 2014; doi:10.1152/ajpheart.00081.2014.-Cholesterol-rich caveolar microdomains and associated caveolins influence sarcolemmal ion channel and receptor function and protective stress signaling. However, the importance of membrane cholesterol content to cardiovascular function and myocardial responses to ischemiareperfusion (I/R) and cardioprotective stimuli are unclear. We assessed the effects of graded cholesterol depletion with methyl-␤-cyclodextrin (M␤CD) and lifelong knockout (KO) or overexpression (OE) of caveolin-3 (Cav-3) on cardiac function, I/R tolerance, and opioid receptor (OR)-mediated protection. Langendorff-perfused hearts from young male C57Bl/6 mice were untreated or treated with 0.02-1.0 mM M␤CD for 25 min to deplete membrane cholesterol and disrupt caveolae. Hearts were subjected to 25-min ischemia/45-min reperfusion, and the cardioprotective effects of morphine applied either acutely or chronically [sustained ligand-activated preconditioning (SLP)] were assessed. M␤CD concentration dependently reduced normoxic contractile function and postischemic outcomes in association with graded (10 -30%) reductions in sarcolemmal cholesterol. Cardioprotection with acute morphine was abolished with Ն20 M M␤CD, whereas SLP was more robust and only inhibited with Ն200 M M␤CD. Deletion of Cav-3 also reduced, whereas Cav-3 OE improved, myocardial I/R tolerance. Protection via SLP remained equally effective in Cav-3 KO mice and was additive with innate protection arising with Cav-3 OE. These data reveal the membrane cholesterol dependence of normoxic myocardial and coronary function, I/R tolerance, and OR-mediated cardioprotection in murine hearts (all declining with cholesterol depletion). In contrast, baseline function appears insensitive to Cav-3, whereas cardiac I/R tolerance parallels Cav-3 expression. Novel SLP appears unique, being less sensitive to cholesterol depletion than acute OR protection and arising independently of Cav-3 expression.cardioprotection; caveolae; caveolin-3; cholesterol; contractility; ischemia-reperfusion; membrane microdomains; opioid receptors SARCOLEMMAL MICRODOMAINS are critical regulators of cellular function and signaling (34) and may be important in sex-, age-, and disease-dependent differences in cardiac and vascular function (3,10,11,14,24,49,62). Caveolae are lipid rich (i.e., cholesterol and glycosphingolipid) microdomains containing scaffolding proteins, caveolins, that present as distinct molecular platforms for the regulation of cytoprotective and other signaling (52). However, the importance of membrane cholesterol and microdomains to the maintenance of myocardial and coronary function as well as intrinsic responses to insult/stress a...

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“…We propose that these interactions occur in caveolae of the invadopodial compartment and are responsible for an increased ECM degradative activity. Indeed, caveolae are membrane domains that 'build' protein-protein signalling complexes (Harvey and Calaghan, 2012) that are required for both invadopodia formation and ECM degradative activity (Caldieri et al, 2012;Caldieri et al, 2009;Yamaguchi et al, 2009). As such, caveolae could be a signalling platform in invadopodia for Na V -and NHE-1-dependent cancer cell invasiveness.…”

Section: Resultsmentioning

confidence: 99%

NaV1.5 sodium channels allosterically regulate the NHE-1 exchanger and promote breast cancer cell invadopodial activity

Brisson

Driffort

Benoist

et al. 2013

Journal of Cell Science

137

153

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SummaryThe degradation of the extracellular matrix by cancer cells represents an essential step in metastatic progression and this is performed by cancer cell structures called invadopodia. Na V 1.5 (also known as SCN5A) Na + channels are overexpressed in breast cancer tumours and are associated with metastatic occurrence. It has been previously shown that Na V 1.5 activity enhances breast cancer cell invasiveness through perimembrane acidification and subsequent degradation of the extracellular matrix by cysteine cathepsins. Here, we show that Na V 1.5 colocalises with Na + /H + exchanger type 1 (NHE-1) and caveolin-1 at the sites of matrix remodelling in invadopodia of MDA-MB-231 breast cancer cells. NHE-1, Na V 1.5 and caveolin-1 co-immunoprecipitated, which indicates a close association between these proteins. We found that the expression of Na V 1.5 was responsible for the allosteric modulation of NHE-1, rendering it more active at the intracellular pH range of 6.4-7; thus, it potentially extrudes more protons into the extracellular space. Furthermore, Na V 1.5 expression increased Src kinase activity and the phosphorylation (Y421) of the actin-nucleation-promoting factor cortactin, modified F-actin polymerisation and promoted the acquisition of an invasive morphology in these cells. Taken together, our study suggests that Na V 1.5 is a central regulator of invadopodia formation and activity in breast cancer cells.

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

Cited by 90 publications

References 122 publications

Osmotic Stress Reduces Ca2+ Signals through Deformation of Caveolae

Osmotic Stress Reduces Ca2+ Signals through Deformation of Caveolae

Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection

NaV1.5 sodium channels allosterically regulate the NHE-1 exchanger and promote breast cancer cell invadopodial activity

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