Item type:Thesis, Open Access

Die physiologische Funktion von TRPC6 in Endothelzellen und glatten Muskelzellen der Lunge

Thumbnail Image

Files

dhk.pdf (2.93 MB)

Date

2009-10-08

relationships.isAuthorOf

Publisher

Philipps-Universität Marburg
DOI

item.page.supervisor-of-thesis

Abstract

The aim of this study was to clarify the molecular mechanisms of hypoxic pulmonary vasoconstriction in precapillary arterial pulmonary smooth muscle cells (PASMC) and ischemia-reperfusion injury in lung endothelial cells (LEC). TRPC6-activation is essential for both mechanisms, because they are abolished in TRPC6-deficient mice. To investigate the mechanisms at the cellular level PASMC and LEC were isolated and their identity confirmed by specific antibodies. Components of the signalling cascade in both cell types were identified by monitoring the Ca2+-increase in response to the application of hypoxic solutions. Important key components of the signal transduction cascades in addition to TRPC6 were identified by the application of specific inhibitors and sensors to the cells. In summary, activation of receptors by nanomolar agonist concentrations (priming) results in a low level of diacylglycerol (DAG) production, which is not able to activate TRPC6 channels, but is rapidly degraded by DAG-kinases. After application of hypoxia, however, production of reactive oxygen species results in DAG-kinase inhibition and sufficient DAGaccumulation to induce TRPC6-activation. The bulk of Ca2+ influx in PASMC responsible for contraction enters through L-type voltage gated Ca2+ channels. These are activated by the depolarisation resulting from Na+ influx through TRPC6- channels. A similar signal transduction cascade exists in LEC, although it is unclear whether a priming event is necessary. In these cells, TRPC6 channels mediate the Ca2+ influx, because L-type voltage gated calcium channels are not expressed. Therefore, TRPC6 is an important perspective pharmacological target for acute hypoxic pulmonary vasoconstriction in PASMC and ischemia-reperfusion injury in LEC.

Review

Metadata

Contributors
Supervisor:
Dates
Created: 2009Issued: 2009-10-08Updated: 2011-08-10
DOI
https://doi.org/10.17192/z2009.0514
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
EndotheliumTransient receptor potentialFuraTRPC6
DFG-subjects
Glatte MuskulaturHypertonieEndothel
DDC-Numbers
610
License
https://rightsstatements.org/vocab/InC-NC/1.0/
URI
https://open.uni-marburg.de/handle/10.17192/z2009.0514
show more
Kalwa, Hermann: Die physiologische Funktion von TRPC6 in Endothelzellen und glatten Muskelzellen der Lunge. : Philipps-Universität Marburg 2009-10-08. DOI: https://doi.org/10.17192/z2009.0514.

License

item.page.license.under-copyright
This item has been published with the following license: In Copyright