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E-Conference: Defining Calcium Entry Signals

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TRPC channels and the second messengers that regulate them

23 June 2004

Randen L. Patterson

A few comments in response to Raghu,

Perhaps I was not clear when I stated very few researchers are looking at endogenous TRPC channels, I should have included mammalian TRPC channels.........

As for this comment "In the meantime, although an enormous variety of thoughtful experiments have been done in mammalian cell lines to address the equivalent question, no one seems to have bothered to do the following experiment; analyse the activation of an endogenous TRPC channel in loss- of-function mutants in the three mammalian InsP3Rs within the context of a well-defined endogenous signalling cascade. Therefore with respect to the role of InsP3R activity in activating TRPC channels, until such an experiment is done, it is perhaps less meaningful to conclude that “Since TRPC channels have evolved quite significantly from fly, it is it is unreasonable to think that they would have to retain the same activation mechanisms that are used in fly.” (Randen Patterson, 12 June comment 4)."

These experiemnts have been done in DT40 IP3R k/o cells(Vazquez et al JBC 2003). They demonstrated that overexpressed TRPC3 channels cannot be activated by receptor alone in these cells. Overexpression of type3 IP3R with TRPC3 rescued TRPC3 activity in response to agonist. We also showed that all calcium entry in response to IgM in these cells was dependent upon IP3 binding to the IP3R, not calcium release from the IP3R (van Rossum et al PNAS 2004) so I would say that this has in fact been tested, and demonstrates a requirement for the IP3R for the activation of mammalian TRPC channels.

In light of this data, coupled to the rigorous work of Kiselyov demonstrating by electrophysiology that the N-terminus of IP3R gates TRPC3 through its binding to IP3, there seems to be a large divergance from the fly TRPC channels to the mammalian channels.

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