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Elucidation of a TRPC6-TRPC5 channel cascade that restricts endothelial cell movement
Pinaki Chaudhuri1, Scott M Colles, Manjunatha Bhat
1Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH 44195, USA.
Abstract:
Canonical transient receptor potential (TRPC) channels are opened by classical signal transduction events initiated by receptor activation or depletion of intracellular calcium stores. Here, we report a novel mechanism for opening TRPC channels in which TRPC6 activation initiates a cascade resulting in TRPC5 translocation. When endothelial cells (ECs) are incubated in lysophosphatidylcholine (lysoPC), rapid translocation of TRPC6 initiates calcium influx that results in externalization of TRPC5. Activation of this TRPC6-5 cascade causes a prolonged increase in intracellular calcium concentration ([Ca(2+)](i)) that inhibits EC movement. When TRPC5 is down-regulated with siRNA, the lysoPC-induced rise in [Ca(2+)](i) is shortened and the inhibition of EC migration is lessened. When TRPC6 is down-regulated or EC from TRPC6(-/-) mice are studied, lysoPC has minimal effect on [Ca(2+)](i) and EC migration. In addition, TRPC5 is not externalized in response to lysoPC, supporting the dependence of TRPC5 translocation on the opening of TRPC6 channels. Activation of this novel TRPC channel cascade by lysoPC, resulting in the inhibition of EC migration, could adversely impact on EC healing in atherosclerotic arteries where lysoPC is abundant.
Insights
Lysophosphatidylcholine (lysoPC) activates a novel TRPC6-TRPC5 channel cascade in endothelial cells, inhibiting their movement. This TRPC channel activation pathway impairs endothelial cell healing, particularly in atherosclerosis.
Area of Science:
- Cell Biology
- Ion Channels
- Cardiovascular Research
Background:
- Canonical transient receptor potential (TRPC) channels are crucial in cellular signaling, typically activated by receptor stimulation or calcium store depletion.
- Lysophosphatidylcholine (lysoPC) is implicated in cardiovascular diseases and influences endothelial cell function.
Purpose of the Study:
- To elucidate a novel mechanism of TRPC channel activation.
- To investigate the role of TRPC6 and TRPC5 channels in endothelial cell response to lysoPC.
- To determine the impact of this pathway on endothelial cell migration and potential implications in atherosclerosis.
Main Methods:
- Utilized endothelial cells (ECs) and lysophosphatidylcholine (lysoPC) stimulation.
- Investigated TRPC6 and TRPC5 channel translocation and activation using techniques like siRNA and knockout mice.
- Measured intracellular calcium concentration ([Ca(2+)](i)) and endothelial cell migration.
Main Results:
- LysoPC induces TRPC6 translocation, initiating calcium influx and subsequent TRPC5 externalization, forming a TRPC6-5 cascade.
- This cascade leads to a sustained increase in [Ca(2+)](i), inhibiting EC migration.
- Downregulation of TRPC5 or TRPC6 significantly reduces the lysoPC-induced calcium rise and mitigates the inhibition of EC migration.
- TRPC5 translocation is dependent on TRPC6 channel opening.
Conclusions:
- A novel lysoPC-activated TRPC channel cascade involving TRPC6 and TRPC5 has been identified.
- This pathway inhibits endothelial cell migration, potentially impairing vascular healing.
- The findings suggest a significant role for this TRPC channel cascade in the context of atherosclerosis.
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