Mouse transient receptor potential channel 6: Role in hemostasis and thrombogenesis

Espinosa, Enma Veronica Paez; Murad, John P.; Ting, Harold J.; Khasawneh, Fadi T.

doi:10.1016/j.bbrc.2011.12.058

Cited by 32 publications

(38 citation statements)

References 30 publications

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“…TRPC6 is up-regulated in several acquired proteinuric kidney diseases (15), transgenic overexpression of wild-type or mutant TRPC6 in podocytes induces a mild glomerular phenotype (16), and TRPC6-deficient mice show some resistance to angiotensin II-induced proteinuria (17). TRPC6 has also been implicated in regulating blood pressure (18), pulmonary vascular tone and permeability (19 -24), cardiac hypertrophy (25)(26)(27), myofibroblast differentiation and associated wound healing (28,29), neuronal growth cone guidance (30), and platelet function (31). Why mutations in TRPC6 lead specifically to kidney disease is unknown.…”

Section: Gain-of-function Mutations In the Canonical Transient Receptmentioning

confidence: 99%

Gain-of-function Mutations in Transient Receptor Potential C6 (TRPC6) Activate Extracellular Signal-regulated Kinases 1/2 (ERK1/2)

Chiluiza

Krishna

Schumacher

et al. 2013

Journal of Biological Chemistry

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Background: Signaling events affected by disease-associated mutations in TRPC6 are poorly defined. Results: Expression of mutant TRPC6 induces ERK1/2 activation via both cell-autonomous and non-cell-autonomous mechanisms. Conclusion: Mutant TRPC6 activates complex signaling pathways that lead to the release of paracrine factors activating ERK. Significance: Understanding the signaling pathways downstream of gain-of-function TRPC6 is crucial for understanding TRPC6-mediated biology and pathology.

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Section: Gain-of-function Mutations In the Canonical Transient Receptmentioning

confidence: 99%

Gain-of-function Mutations in Transient Receptor Potential C6 (TRPC6) Activate Extracellular Signal-regulated Kinases 1/2 (ERK1/2)

Chiluiza

Krishna

Schumacher

et al. 2013

Journal of Biological Chemistry

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“…No alteration of platelet Ca 2+ responses or functional responses could be detected by one group in platelets from mice deficient in either TRPC1 or TRPC6 [99,104]. However, a brief report from another group found that deletion of TRPC6 in mice led to a small increase in bleeding time and a small reduction in arterial thrombosis [106]. Cation channels activated independently of store depletion, for which TRPC6 is a major candidate, have been suggested to play a greater role at higher concentrations of thrombin [107], thus their relative contribution to platelet activation may vary with the strength or type of stimulus and explain the difference between the two murine studies [104,106].…”

Section: Transient Receptor Potential Ion Channelsmentioning

confidence: 99%

The unique contribution of ion channels to platelet and megakaryocyte function

Mahaut‐Smith

2012

Journal of Thrombosis and Haemostasis

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Summary. Ion channels are transmembrane proteins that play ubiquitous roles in cellular homeostasis and activation. In addition to their recognized role in the regulation of ionic permeability and thus membrane potential, some channel proteins possess intrinsic kinase activity, directly interact with integrins or are permeable to molecules up to ≈1000 Da. The small size and anuclear nature of the platelet has often hindered progress in understanding the role of specific ion channels in hemostasis, thrombosis and other platelet‐dependent events. However, with the aid of transgenic mice and ‘surrogate’ patch clamp recordings from primary megakaryocytes, important unique contributions to platelet function have been identified for several classes of ion channel. Examples include ATP‐gated P2X1 channels, Orai1 store‐operated Ca2+ channels, voltage‐gated Kv1.3 channels, AMPA and kainate glutamate receptors and connexin gap junction channels. Furthermore, evidence exists that some ion channels, such as NMDA glutamate receptors, contribute to megakaryocyte development. This review examines the evidence for expression of a range of ion channels in the platelet and its progenitor cell, and highlights the distinct roles that these proteins may play in health and disease.

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“…Hemostasis was measured using the tail transection technique, following previously established protocols . Briefly, 5 months old mice were separated in two groups: LIGHT −/− ( n = 5) and C57BL/6 ( n = 5) were anesthetized by an intraperitoneal injection of ketamine (80 mg/kg) and xylazine (16 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

“…Hemostasis was measured using the tail transection technique, following previously established protocols. 29,30 Briefly, 5 months old mice were separated in two groups: LIGHT 2/2 (n 5 5) and C57BL/6 (n 5 5) were anesthetized by an intraperitoneal injection of ketamine (80 mg/kg) and xylazine (16 mg/kg). Mice were placed on a 37 8C heating blanket (Harvard Apparatus Limited, Edenbridge, KY) before the tail was transected using a sterile scalpel to make a clean cut at a distance of 5 mm from the tip.…”

Section: Tail Bleeding Timementioning

confidence: 99%

Arachidonic acid‐derived signaling lipids and functions in impaired healing

Dhall

Wijesinghe

Karim

et al. 2015

Wound Repair Regeneration

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Very little is known about lipid function during wound healing, and much less during impaired healing. Such understanding will help identify what roles lipid signaling plays in the development of impaired/chronic wounds. We took a lipidomics approach to study the alterations in lipid profile in the LIGHT−/− mouse model of impaired healing which has characteristics that resemble those of impaired/chronic wounds in humans, including high levels of oxidative stress, excess inflammation, increased extracellular matrix degradation and blood vessels with fibrin cuffs. The latter suggests excess coagulation and potentially increased platelet aggregation. We show here that in these impaired wounds there is an imbalance in the arachidonic acid (AA) derived eicosonoids that mediate or modulate inflammatory reactions and platelet aggregation. In the LIGHT−/− impaired wounds there is a significant increase in enzymatically derived breakdown products of AA. We found that early after injury there was a significant increase in the eicosanoids 11-, 12-, and 15-hydroxyeicosa-tetranoic acid, and the proinflammatory leukotrienes (LTD4 and LTE) and prostaglandins (PGE2 and PGF2α). Some of these eicosanoids also promote platelet aggregation. This led us to examine the levels of other eicosanoids known to be involved in the latter process. We found that thromboxane (TXA2/B2), and prostacyclins 6kPGF1α are elevated shortly after wounding and in some cases during healing. To determine whether they have an impact in platelet aggregation and hemostasis, we tested LIGHT−/− mouse wounds for these two parameters and found that, indeed, platelet aggregation and hemostasis are enhanced in these mice when compared with the control C57BL/6 mice. Understanding lipid signaling in impaired wounds can potentially lead to development of new therapeutics or in using existing nonsteroidal anti-inflammatory agents to help correct the course of healing.

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Mouse transient receptor potential channel 6: Role in hemostasis and thrombogenesis

Cited by 32 publications

References 30 publications

Gain-of-function Mutations in Transient Receptor Potential C6 (TRPC6) Activate Extracellular Signal-regulated Kinases 1/2 (ERK1/2)

Gain-of-function Mutations in Transient Receptor Potential C6 (TRPC6) Activate Extracellular Signal-regulated Kinases 1/2 (ERK1/2)

The unique contribution of ion channels to platelet and megakaryocyte function

Arachidonic acid‐derived signaling lipids and functions in impaired healing

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