TRPC6 is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response

Weber, Evan W.; Han, Fei; Tauseef, Mohammad; Birnbaumer, Lutz; Mehta, Dolly; Müller, William A.

doi:10.1083/jcb.2107oia192

Cited by 3 publications

(10 citation statements)

References 32 publications

(42 reference statements)

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Section: Initiating Transmigration: Major Signaling Eventsmentioning

confidence: 99%

“…Further evidence came when we found that chelation of endothelial Ca 2+ inhibited targeted recycling of the LBRC to the same extent that it inhibited TEM . Transient receptor potential canonical family member six (TRPC6) is a non‐selective cation channel that is fivefold more permeable to Ca 2+ than Na + .…”

Section: Initiating Transmigration: Major Signaling Eventsmentioning

confidence: 99%

“…Live imaging confirms what was suspected from transmission and scanning electron micrographs : that the leukocytes are actively moving along the endothelial borders probing with lamellipodia, as if looking for a spot to transmigrate. There is no change in the ability of neutrophils, monocytes, or lymphocytes to adhere to the endothelial cells or move to the junctions; only TEM is inhibited .…”

Section: Initiating Transmigration: Major Signaling Eventsmentioning

confidence: 99%

“…Transient receptor potential canonical family member six (TRPC6) is a non‐selective cation channel that is fivefold more permeable to Ca 2+ than Na + . It is the most abundant TRPC channel in endothelial cells and is concentrated along endothelial cell borders, where it seems to be further enriched in the endothelial membrane surrounding transmigrating PMN .…”

Section: Initiating Transmigration: Major Signaling Eventsmentioning

confidence: 99%

“…Expression of a dominant negative TRPC6 or knockdown of endogenous TRPC6 in human umbilical vein endothelial cells dramatically reduced targeted recycling of the LBRC and TEM of PMN and monocytes . Both processes were restored in endothelial cells by expression of a rescue construct expressing TRPC6 resistant to the shRNA . In TRPC6‐deficient mice reconstituted with wildtype bone marrow, PMNs were still recruited to a site of inflammation in the skin, but there was a selective defect in transmigration .…”

Section: Initiating Transmigration: Major Signaling Eventsmentioning

confidence: 99%

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Transendothelial migration: unifying principles from the endothelial perspective

Müller

2016

Immunological Reviews

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Summary Transendothelial migration (TEM) of PMN involves a carefully orchestrated dialogue of adhesion and signaling events between leukocyte and endothelial cell. This chapter will focus on the endothelial cells’ contribution to transmigration. The initiation of TEM itself generally requires interaction of PECAM on the leukocyte with PECAM at the endothelial cell border. This is responsible for the transient elevation of cytosolic free calcium ions in endothelium that is required for TEM and for recruitment of membrane from the lateral border recycling compartment (LBRC). TEM requires LBRC to move to the site at which TEM will take place and for VE-cadherin to move away. Targeting of the LBRC to this site likely precedes movement of VE-cadherin, and may play a role in clearing VE-cadherin from the site of TEM. The process of TEM can be dissected into steps mediated by distinct pairs of PMN/endothelial interacting molecules. CD99 regulates a step at or close to the end of TEM. CD99 signals through soluble adenylyl cyclase to activate PKA to trigger ongoing targeted recycling of the LBRC. Paracellular transmigration predominates (≥ 90% of events) in the cremaster muscle circulation, but transcellular migration may be more important at sites such as the blood brain barrier. Both processes involve many of the same molecules as well as recruitment of the LBRC.

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Section: Initiating Transmigration: Major Signaling Eventsmentioning

confidence: 99%

Section: Initiating Transmigration: Major Signaling Eventsmentioning

confidence: 99%

Section: Initiating Transmigration: Major Signaling Eventsmentioning

confidence: 99%

Section: Initiating Transmigration: Major Signaling Eventsmentioning

confidence: 99%

Section: Initiating Transmigration: Major Signaling Eventsmentioning

confidence: 99%

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Transendothelial migration: unifying principles from the endothelial perspective

Müller

2016

Immunological Reviews

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132

122

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CD99L2 deficiency inhibits leukocyte entry into the central nervous system and ameliorates neuroinflammation

Samus

Seelige

Schäfer

et al. 2018

Journal of Leukocyte Biology

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Leukocyte entry into the CNS is a crucial step in the development of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Adhesion molecules mediating the docking of leukocytes to the endothelium of the blood-brain barrier (BBB) represent valuable targets for interference with the disease. However, little is known about the adhesion and signaling mechanisms in endothelial cells that mediate the diapedesis through the BBB. Here, we show that conditional Tie-2-Cre driven gene inactivation of CD99L2 inhibits leukocyte entry into the CNS during active MOG -induced EAE and alleviates severity of the disease. No detrimental effect on the immune response was observed. The number of perivascular cuffs around vessels of the CNS was reduced, as was the number of inflammatory foci, sites of demyelination and expression levels of pro-inflammatory cytokines. Three-dimensional analysis of vibratome sections of the CNS revealed an accumulation of leukocytes between endothelial cells and the underlying basement membrane, whereas leukocyte docking to the luminal surface of the endothelium of the BBB was unaffected. Collectively, these results suggest that CD99L2 participates in the development of EAE by supporting diapedesis of leukocytes through the endothelial basement membrane of blood vessels of the BBB in the CNS.

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The activity of transient receptor potential channel C‐6 modulates the differentiation of fat cells

et al. 2019

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Previously, the V1‐3 isoforms of the transient receptor potential channel (TRP) have been shown to promote or prevent adipocyte differentiation. In the current study, the C isoforms were screened for blocking adipogenesis. The hypothesis that the TRP classic or canonical (TRPC) deters adipocyte differentiation was investigated in 3T3‐L1 cells employing the channel‐specific activator and antagonist, silencing, and overexpression techniques. Fat accumulation in cells was visualized by Oil Red O staining. Intracellular calcium inflow was estimated by confocal microscopy. A high‐fat (HF) feeding study was also performed on C57BL/6J mice to verify the findings in the cell model. Among the 6 C isoforms tested, only TRPC‐6 inhibited the differentiation of fat cells. The phytochemical quercetin induced the channel protein expression. Calcium‐imaging results also revealed that the flavonoid could trigger calcium inflow. Coadministration of quercetin (1 or 20 mg/kg body weight) in an HF diet prevented TRPC‐6 from declining and attenuated phosphorylated (p)‐PKB and PI3k, as well as the proliferation of visceral fat cells. The present study illustrated that TRPC‐6 activation could perturb adipocyte differentiation. The food f lavonoid quercetin was a TRPC‐6 inducer and activator and it could prevent adipogenesis in mice.—Tan, Y. Q., Kwan, H. Y., Yao, X., Leung, L. K. The activity of transient receptor potential channel C‐6 modulates the differentiation of fat cells. FASEB J. 33, 6526–6538 (2019). http://www.fasebj.org

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TRPC6 is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response

Cited by 3 publications

References 32 publications

Transendothelial migration: unifying principles from the endothelial perspective

Transendothelial migration: unifying principles from the endothelial perspective

CD99L2 deficiency inhibits leukocyte entry into the central nervous system and ameliorates neuroinflammation

The activity of transient receptor potential channel C‐6 modulates the differentiation of fat cells

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