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The most well-known inositol, IP3, has three phosphates attached, and is produced in the cell in response to stimuli, via the action of a key enzyme called phospholipase C. IP3 is known to be critical for triggering the release of calcium, which in turn triggers other cell processes.

However, York and his colleagues to their surprise had found that IP3 apparently has yet unknown extended signaling roles, produced when additional phosphates are added to produce IP4, IP5 and IP6 in the cell. Production of these IPs also depends on phospholipase C activity in cells.

The latest research began when York contacted Wente, after learning through colleague Jeremy Thorner of the University of California-Berkeley that Wente had discovered a link between a phospholipase C and an essential factor GLe-1 that is essential for transporting mRNA out of the nucleus. Of particular interest was that Wente had also discovered that two other genes of unknown function also linked to GLe-1.

York theorized that the other two genes might be the blueprints for two new kinases responsible for adding phosphates to IP3 on the way to producing IP6.

"It was easy to test this hypothesis," said York. "We just introduced radio-labeled inositol into yeast strains mutated to lack the genes for one or the other of the suspected kinases. Depending on the kinase blocked, we expected to see buildup of either IP3 or IP5, with no IP6 in any case." Sure enough, said York, the experiments indicated that the mysterious genes coded for kinases, or at least their regulators, transformed IP3 to IP4, and IP5 to IP6.

According to York, still to be determined is whether IP6 directly or indirectly affects the transport of mRNA from the nucleus. IP6 may merely regulate the "gatekeeper" -
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Contact: Dennis Meredith
Dennis.meredith@duke.edu
919-681-8054
Duke University
2-Jul-1999