Inhibition of PKCα and rhoA Translocation in Differentiated Smooth Muscle by a Caveolin Scaffolding Domain Peptide

Taggart, Michael J.; Leavis, Paul C.; Féron, Olivier; Morgan, Kathleen G.

doi:10.1006/excr.2000.4891

Cited by 73 publications

(73 citation statements)

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“…Cardiomyocytes express multiple PKC subtypes that play key roles in a spectrum of adaptive and maladaptive cardiac responses including the development of hypertrophy [18]. In vitro experiments by using caveolin scaffolding domain peptides demonstrated a potent inhibition of PKC kinase activity or the translocation of PKC upon activation by growth factor stimulation [8,19]. PKC subtypes are located in caveolae and are inhibited by caveolin-3; however, this inhibition occurred in a PKCsubtype specific manner [8].…”

Section: Discussionmentioning

confidence: 99%

Caveolin‐3 inhibits growth signal in cardiac myoblasts in a Ca²⁺‐dependent manner

Fujita

Otsu

Oshikawa

et al. 2006

J Cellular Molecular Medi

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Caveolin, a major protein component of caveolae, directly interacts with multiple signaling molecules, such as Ras and growth factor receptors, and inhibits their function. However, the role of the second messenger system in mediating this inhibition by caveolin remains poorly understood. We examined the role of Ca 2+ -dependent signal in caveloin-mediated growth inhibition using a rat cardiac myoblast cell line (H9C2), in which the expression of caveolin-3, the muscle specific subtype, can be induced using the LacSwitch system. Upon induction with IPTG and serum-starvation, the expression of caveolin-3 was increased by 3.3-fold relative to that of mock-induced cells. The recombinant caveolin-3 was localized to the same subcellular fraction as endogenous caveolin-3 after sucrose gradient purification. Angiotensin II enhanced ERK phosphorylation, but this enhancement was significantly decreased in caveolin-3-induced cells in comparison to that in mock-induced cells. Similarly, when cells were stimulated with fetal calf serum, DNA synthesis, as determined by [ 3 H]-thymidine incorporation, was significantly decreased in caveolin-3-induced cells. When cells were treated with Ca 2+ chelator (BAPTA and EGTA), however, this attenuation was blunted. Calphostin (PKC inhibitor), but not cyclosporine A treatment (calcineurin inhibitor), blunted this attenuation in caveolin-3 induced cells. Our findings suggest that caveolin exhibits growth inhibition in a Ca 2+ -dependent manner, most likely through PKC, in cardiac myoblasts.

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Section: Discussionmentioning

confidence: 99%

Caveolin‐3 inhibits growth signal in cardiac myoblasts in a Ca²⁺‐dependent manner

Fujita

Otsu

Oshikawa

et al. 2006

J Cellular Molecular Medi

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“…Interestingly, both Cav-1 and Cav-2 are present in arterial smooth muscle, but venous smooth muscle contains only Cav-1 [Segal et al, 1999]. Furthermore, while smooth muscle cells from the ileum, stomach, and uterus express all three caveolins [Taggart et al, 2000], Cav-2 and Cav-3 are not present in aortic smooth muscle [Je et al, 2003] and papillary dilator muscle [Kogo et al, 2006], respectively. In the eye and colon, Cav-3 was detected in the papillary sphincter muscle and inner circular layer, but not in the ciliary muscle or outer longitudinal layer [Kogo et al, 2006].…”

Section: Introductionmentioning

confidence: 99%

Smooth muscle caveolae differentially regulate specific agonist induced bladder contractions

Cristofaro

Peters

Yalla

et al. 2006

Neurourology and Urodynamics

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Aims: Caveolae are cholesterol-rich plasmalemmal microdomains that serve as sites for sequestration of signaling proteins and thus may facilitate, organize, and integrate responses to extracellular stimuli. While previous studies in the bladder have demonstrated alterations in caveolae with particular physiologic or pathologic conditions, little attention has been focused on the functional signi¢cance of these organelles. Therefore, the purpose of this study was to investigate the role of caveolae in the modulation of receptor-mediated signal transduction and determine the presence and localization of caveolin proteins in bladder tissue. Methods: Contractile responses to physiologic agonists were measured in rat bladder tissue before and after disruption of caveolae achieved by depleting membrane cholesterol with methyl-b-cyclodextrin. Stimulation with agonists was repeated after caveolae were restored as a result of cholesterol replenishment. RT-PCR, immmunohistochemistry, and Western blotting were used to determine the expression and localization of caveolin mRNA and proteins. Results: Following caveolae disruption, contractile responses to angiotensin II and serotonin were attenuated, whereas responses to bradykinin and phenylephrine were augmented. Cholesterol replenishment restored responses towards baseline. Carbachol and KCl induced contractions were not a¡ected by caveolae disruption. Ultrastructure analysis con¢rmed loss of caveolae following cholesterol depletion with cyclodextrin and caveolae restoration following cholesterol replacement. Gene and protein expression of caveolin-1, -2, and -3 was detected in bladder tissue. Immunoreactivity for all three caveolins was observed in smooth muscle cells throughout the bladder. Conclusions: The functional e¡ects of cholesterol depletion on speci¢c agonist-induced contractile events and the expression of all three caveolins in bladder smooth muscle support a central role for caveolae in regulation of selective G-protein-coupled receptor signaling pathways in bladder smooth muscle. Thus, caveolae serve to di¡erentially regulate bladder smooth muscle by a stimulus-dependent potentiation or inhibition of bladder contraction.

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“…Large conductance, voltage-and Ca 2ϩ -activated potassium (MaxiK, BK) 4 channels play important roles in vascular, neuronal, and urinary functions. In vascular smooth muscle, MaxiK channel appears to be a unique signaling protein because of its ability to mediate the effects of several vasoconstricting as well as vasodilating agents.…”

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confidence: 99%

“…All of them seem to be expressed in smooth muscle (3,4). However, gene ablation experiments have shown that caveolin-1 plays a major role in the vasculature and pulmonary function.…”

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confidence: 99%

Slo1 Caveolin-binding Motif, a Mechanism of Caveolin-1-Slo1 Interaction Regulating Slo1 Surface Expression

Alioua¹,

Lü²,

Kumar³

et al. 2008

Journal of Biological Chemistry

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The large conductance, voltage-and Ca 2؉ -activated potassium (MaxiK, BK) channel and caveolin-1 play important roles in regulating vascular contractility. Here, we hypothesized that the MaxiK ␣-subunit (Slo1) and caveolin-1 may interact with each other. Slo1 and caveolin-1 physiological association in native vascular tissue is strongly supported by (i) detergent-free purification of caveolin-1-rich domains demonstrating a pool of aortic Slo1 co-migrating with caveolin-1 to light density sucrose fractions, (ii) reverse co-immunoprecipitation, and (iii) double immunolabeling of freshly isolated myocytes revealing caveolin-1 and Slo1 proximity at the plasmalemma. In HEK293T cells, Slo1-caveolin-1 association was unaffected by the smooth muscle MaxiK ␤1-subunit. Sequence analysis revealed two potential caveolin-binding motifs along the Slo1 C terminus, one equivalent, 1007 YNMLCFGIY 1015 , and another mirror image, 537 YT-EYLSSAF 545 , to the consensus sequence, XXXX XX . Deletion of 1007 YNMLCFGIY 1015 caused ϳ80% loss of Slo1-caveolin-1 association while preserving channel normal folding and overall Slo1 and caveolin-1 intracellular distribution patterns. 537 YTEYLSSAF 545 deletion had an insignificant dissociative effect. Interestingly, caveolin-1 coexpression reduced Slo1 surface and functional expression near 70% without affecting channel voltage sensitivity, and deletion of 1007 YNMLCF-GIY 1015 motif obliterated channel surface expression. The results suggest 1007 YNMLCFGIY 1015 possible participation in Slo1 plasmalemmal targeting and demonstrate its role as a main mechanism for caveolin-1 association with Slo1 potentially serving a dual role: (i) maintaining channels in intracellular compartments downsizing their surface expression and/or (ii) serving as anchor of plasma membrane resident channels to caveolin-1-rich membranes. Because the caveolin-1 scaffolding domain is juxtamembrane, it is tempting to suggest that Slo1-caveolin-1 interaction facilitates the tethering of the Slo1 C-terminal end to the membrane.Large conductance, voltage-and Ca 2ϩ -activated potassium (MaxiK, BK) 4 channels play important roles in vascular, neuronal, and urinary functions. In vascular smooth muscle, MaxiK channel appears to be a unique signaling protein because of its ability to mediate the effects of several vasoconstricting as well as vasodilating agents. The ability of MaxiK protein to complete with high fidelity these opposite tasks calls for specific associations and subcellular compartmentalization with corresponding signaling partners (1). Recently, it has been appreciated that many signaling molecules are segregated primarily in specialized microdomains like caveolae (plasma membrane invaginations enriched with cholesterol and caveolin protein), thereby, optimizing signal transduction between agonists and specific effectors (2).Three caveolin proteins have been identified, caveolin-1, -2, and -3. All of them seem to be expressed in smooth muscle (3, 4). However, gene ablation experiments have shown that caveolin-1 p...

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Inhibition of PKCα and rhoA Translocation in Differentiated Smooth Muscle by a Caveolin Scaffolding Domain Peptide

Cited by 73 publications

References 50 publications

Caveolin‐3 inhibits growth signal in cardiac myoblasts in a Ca²⁺‐dependent manner

Caveolin‐3 inhibits growth signal in cardiac myoblasts in a Ca²⁺‐dependent manner

Smooth muscle caveolae differentially regulate specific agonist induced bladder contractions

Slo1 Caveolin-binding Motif, a Mechanism of Caveolin-1-Slo1 Interaction Regulating Slo1 Surface Expression

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Inhibition of PKCα and rhoA Translocation in Differentiated Smooth Muscle by a Caveolin Scaffolding Domain Peptide

Cited by 73 publications

References 50 publications

Caveolin‐3 inhibits growth signal in cardiac myoblasts in a Ca2+‐dependent manner

Caveolin‐3 inhibits growth signal in cardiac myoblasts in a Ca2+‐dependent manner

Smooth muscle caveolae differentially regulate specific agonist induced bladder contractions

Slo1 Caveolin-binding Motif, a Mechanism of Caveolin-1-Slo1 Interaction Regulating Slo1 Surface Expression

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Caveolin‐3 inhibits growth signal in cardiac myoblasts in a Ca²⁺‐dependent manner

Caveolin‐3 inhibits growth signal in cardiac myoblasts in a Ca²⁺‐dependent manner