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E-Conference: Defining Calcium Entry Signals

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TRPC channels and the second messengers that regulate them

4 June 2004

Randen L Patterson

I have a question about this statement "As deduced from pharmacological inhibition of DAG lipase and DAG kinase, endogenously generated DAG is sufficient for channel activation. Most notably, receptor agonists and DAGs do not display additive effects on TRPC3 and TRPC6 current amplitudes, suggesting that the same TRPC channels are activated by DAG and by PLC-linked receptors and that DAG may be the decisive second messenger generated by PLC. "

1)Ma et al. (Science 2000, Figure 2), clearly demonstrated that the DAG could increase the flow of Strontium (Sr2+) through TRPC3 after agonist stimulation.......I would argue that additive effects of DAG can be seen, which would argue for independent mechanisms of DAG and receptor activation of TRPC channels.

2)Pharmacological blockade of DAG breakdown is, in my opinion, no different than the external addition of DAG analogues. The levels that accumulate in response to this inhibition could be micromolar. Similar effects can be seen when using pervanadate to block tyrosine phosphatases. In only a few minutes, ALL tyrosine kinase substrates are highly phosphorylated.

Until direct binding studies of DAG are performed with TRPC channels, it can not be concluded that DAG plays a significant role in their physiological activation, although it is clear that DAG analogues can be used as a tool to manipulate TRPC channel activity.

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