Caveolins: targeting pro-survival signaling in the heart and brain

Stary, Creed M.; Murakami, Yasuo; Patel, Piyush M.; Head, Brian P.; Patel, Hemal H.; Roth, David M.

doi:10.3389/fphys.2012.00393

Cited by 42 publications

(44 citation statements)

References 130 publications

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“…An elaborate network of nodal signaling integrators is activated in response to cardiac stress to promote cardiac hypertrophy as a compensatory response to maintain cardiac output. The signaling pathways associated with caveolae, which compartmentalize receptors, ion channels, and signaling effectors (56,57), have generally been characterized as cardioprotective. The link between caveolae and cardiac hypertrophy was first established in Cav3 KO mice, which display significant hypertrophy, dilation, and reduced fractional shortening associated with hyperactivation of the maladaptive p42/44 MAPK pathway (44).…”

Section: Discussionmentioning

confidence: 99%

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Wei

Sinden

Zhang

et al. 2017

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

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The fibroblast growth factor (FGF) homologous factor FGF13, a noncanonical FGF, has been best characterized as a voltage-gated Na + channel auxiliary subunit. Other cellular functions have been suggested, but not explored. In inducible, cardiac-specific Fgf13 knockout mice, we found-even in the context of the expected reduction in Na + channel current-an unanticipated protection from the maladaptive hypertrophic response to pressure overload. To uncover the underlying mechanisms, we searched for components of the FGF13 interactome in cardiomyocytes and discovered the complete set of the cavin family of caveolar coat proteins. Detailed biochemical investigations showed that FGF13 acts as a negative regulator of caveolae abundance in cardiomyocytes by controlling the relative distribution of cavin 1 between the sarcolemma and cytosol. In cardiac-specific Fgf13 knockout mice, cavin 1 redistribution to the sarcolemma stabilized the caveolar structural protein caveolin 3. The consequent increase in caveolae density afforded protection against pressure overload-induced cardiac dysfunction by two mechanisms: (i) enhancing cardioprotective signaling pathways enriched in caveolae, and (ii) increasing the caveolar membrane reserve available to buffer membrane tension. Thus, our results uncover unexpected roles for a FGF homologous factor and establish FGF13 as a regulator of caveolae-mediated mechanoprotection and adaptive hypertrophic signaling. (1), share a core domain with homology to canonical FGFs, but FHFs are not secreted, do not bind or activate FGF receptors, and do not function as growth factors (2). Instead, FHFs bind directly to voltage-gated Na + channels, modulating channel gating and trafficking (3, 4). Widely expressed in the brain (1), FHFs have been implicated in neurologic diseases such as spinocerebellar ataxia 27, caused by missense mutations in FGF14 that diminish Na + channel current, disrupt channel localization, and impair neuronal excitability (5-7).In addition to their broad distribution in the central nervous system, FHFs are expressed in the mammalian heart (1). Their roles in regulating cardiac function, however, have only been recently investigated. We showed that FGF13, the predominant FHF in rodent heart and a common transcript in human heart (8), directly binds to the C terminus of cardiac Na V 1.5 Na + channels, and thereby regulates current density and conduction velocity by affecting channel gating and surface expression (9). Similarly, mutations that disrupt interaction between Na V 1.5 and FGF12, the major human cardiac FHF, have been linked to lifethreatening arrhythmia syndromes (8, 10). In addition to regulating Na + channels, FHFs can modulate voltage-gated Ca 2+ channels (11, 12). Fgf13 knockdown in adult rodent ventricular cardiomyocytes decreased Ca V 1.2 current density, perturbed Ca V 1.2 localization at the dyad, and thereby affected Ca 2+ -induced Ca 2+ release (11). Because previous studies were conducted in cultured cardiomyocytes, however, the in vivo roles for FHFs in ...

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Section: Discussionmentioning

confidence: 99%

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Wei

Sinden

Zhang

et al. 2017

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

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“…The declining I/R tolerance is not unexpected given the influences of caveolae and cholesterol on key determinants of stress resistance (8,18,31,32,44,(52)(53)(54)(55)(56)(57). For example, M␤CD consistently inhibits BK Ca channel function across different cell types, and the channel has been implicated in cytoprotection and I/R injury.…”

Section: Discussionmentioning

confidence: 99%

“…This may reflect select disruption of caveolae (and dependent G proteincoupled receptors) at low M␤CD levels versus more widespread disruption of membrane lipid rafts at higher concentrations. Non-caveolar planar lipid rafts may be equally important in the membrane signal transduction underlying cytoprotective responses (44,52). It is also important to note that acute and sustained OR stimuli differ in terms of the timing of OR involvement.…”

Section: Discussionmentioning

confidence: 99%

“…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 and protective stimuli is unclear.…”

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confidence: 99%

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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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“…Caveolae are small lipid rafts of the plasma membrane which contribute to cell signalling (Sowa 2011). Caveolae formation and stabilisation depends on the key structural protein, caveolin (Smart et al 1999), which occurs in three isoforms of caveolin 1 to 3 (Cav-1, -2, and -3) (Stary et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine

Bai

Song

et al. 2017

Psychopharmacology

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Here we present the data indicating that chronic treatment with fluoxetine regulates Cav-1/PTEN/PI3K/AKT/GSK-3β signalling pathway and glycogen content in primary cultures of astrocytes with bi-phasic concentration dependence. At lower concentrations fluoxetine down-regulates gene expression of Cav-1, decreases membrane content of PTEN, increases activity of PI3K/AKT, and elevates GSK-3β phosphorylation thus suppressing its activity. At higher concentrations fluoxetine acts in an inverse fashion. As expected, fluoxetine at lower concentrations increased while at higher concentrations decreased glycogen content in astrocytes. Our findings indicate that bi-phasic regulation of glycogen content via Cav-1/PTEN/AKT/GSK-3β pathway by fluoxetine may be responsible for both therapeutic and side effects of the drug.

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Caveolins: targeting pro-survival signaling in the heart and brain

Cited by 42 publications

References 130 publications

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

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

Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine

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