Regulation of Podosome Formation in Macrophages by a Splice Variant of the Sodium Channel SCN8A

Carrithers, Michael D.; Chatterjee, Gouri; Carrithers, Lisette M.; Offoha, Roosevelt; Iheagwara, Uzoma K.; Rahner, Christoph; Graham, Morven; Waxman, Stephen G.

doi:10.1074/jbc.m801892200

Cited by 103 publications

(108 citation statements)

References 36 publications

(44 reference statements)

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“…Na V channels have also been identified in other invasive cells, such as macrophages (Carrithers et al, 2007) and microglial cells (Black and Waxman, 2012), and blocking their activity has been shown to reduce cell invasiveness. It has also been proposed that this effect depends on the regulation of formation of podosomes (Carrithers et al, 2009). …”

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

135

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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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

135

153

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“…Reported activities include enhancement of extracellular proteolysis (58), decreased protein kinase A activity in metastatic cancer cells (59), and Ca 2ϩ release from the mitochondria of mast cells (60). Our study adds a novel dimension to this emerging field: a key role for VGSC activity and membrane potential in the regulation of VEGF-induced EC proliferation via PKC␣ and ERK1/2 (Fig.…”

Section: Reciprocal Signaling Between Pkc And/or Erk1/2 Andmentioning

confidence: 95%

Angiogenic Functions of Voltage-gated Na+ Channels in Human Endothelial Cells

Andrikopoulos

Fraser

Patterson

et al. 2011

Journal of Biological Chemistry

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Voltage-gated sodium channel (VGSC) activity has previously been reported in endothelial cells (ECs). However, the exact isoforms of VGSCs present, their mode(s) of action, and potential role(s) in angiogenesis have not been investigated. The main aims of this study were to determine the role of VGSC activity in angiogenic functions and to elucidate the potentially associated signaling mechanisms using human umbilical vein endothelial cells (HUVECs) as a model system. Real-time PCR showed that the primary functional VGSC ␣-and ␤-subunit isoforms in HUVECs were Nav1.5, Nav1.7, VGSC␤1, and VGSC␤3. Western blots verified that VGSC␣ proteins were expressed in HUVECs, and immunohistochemistry revealed VGSC␣ expression in mouse aortic ECs in vivo. Electrophysiological recordings showed that the channels were functional and suppressed by tetrodotoxin (TTX). VGSC activity modulated the following angiogenic properties of HUVECs: VEGF-induced proliferation or chemotaxis, tubular differentiation, and substrate adhesion. Interestingly, different aspects of angiogenesis were controlled by the different VGSC isoforms based on TTX sensitivity and effects of siRNA-mediated gene silencing. Additionally, we show for the first time that TTX-resistant (TTX-R) VGSCs (Nav1.5) potentiate VEGF-induced ERK1/2 activation through the PKC␣-B-RAF signaling axis. We postulate that this potentiation occurs through modulation of VEGF-induced HUVEC depolarization and [Ca 2؉ ] i . We conclude that VGSCs regulate multiple angiogenic functions and VEGF signaling in HUVECs. Our results imply that targeting VGSC expression/activity could be a novel strategy for controlling angiogenesis.

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“…NCLX is the major pathway for Na + -dependent Ca 2+ efflux in mitochondria [15,16] and it is activated by cytosolic Na + rise [11,17,48,49]. The strong cytosolic and mitochondrial Na + influx following opening of TRPV1 channels accelerates the activity of the mitochondrial exchanger and subsequently enhances the mitochondrial Ca 2+ shuttling.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Privileged crosstalk between TRPV1 channels and mitochondrial calcium shuttling machinery controls nociception

Nita

Caspi

Gudes

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The nociceptive noxious heat-activated receptor - TRPV1, conducts calcium and sodium, thus producing a depolarizing receptor potential, leading to activation of nociceptive neurons. TRPV1-mediated calcium and sodium influx is negatively modulated by calcium, via calcium-dependent desensitization of TRPV1 channels. A mitochondrial Ca uniporter - MCU, controls mitochondrial Ca entry while a sodium/calcium transporter - NCLX shapes calcium and sodium transients by mediating sodium entry into and removing calcium from the mitochondria. The functional interplay between TRPV1, MCU and NCLX, in controlling the cytosolic and mitochondrial calcium and sodium transients and subsequently the nociceptive excitability, is poorly understood. Here, we used cytosolic and mitochondrial fluorescent calcium and sodium imaging together with electrophysiological recordings of TRPV1-induced currents in HEK293T cells and nociceptor-like dissociated rat dorsal root ganglion neurons, while modulating NCLX or MCU expression using specific small interfering RNA (siNCLX). We show that the propagation of the TRPV1-induced cytosolic calcium and sodium fluxes into mitochondria is dependent on coordinated activity of NCLX and MCU. Thus, knocking-down of NCLX triggers down regulation of MCU dependent mitochondrial Ca uptake. This in turn decreases rate and amplitude of TRPV1-mediated cytosolic calcium, which inhibits capsaicin-induced inward current and neuronal firing. TRPV1-mediated currents were fully rescued by intracellular inclusion of the fast calcium chelator BAPTA. Finally, NCLX controls capsaicin-induced cell death, by supporting massive mitochondrial Ca shuttling. Altogether, our results suggest that NCLX, by regulating cytosolic and mitochondrial ionic transients, modulates calcium-dependent desensitization of TRPV1 channels, thereby, controlling nociceptive signaling.

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Regulation of Podosome Formation in Macrophages by a Splice Variant of the Sodium Channel SCN8A

Cited by 103 publications

References 36 publications

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

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

Angiogenic Functions of Voltage-gated Na+ Channels in Human Endothelial Cells

Privileged crosstalk between TRPV1 channels and mitochondrial calcium shuttling machinery controls nociception

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