Cell Biology

Can You Hear Me Now?

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Science  14 Nov 2008:
Vol. 322, Issue 5904, pp. 1027
DOI: 10.1126/science.322.5904.1027b

It's a bit like talking to your neighbor at a dinner party with a megaphone, but Tovey et al. report that the stimulation of calcium release through inositol 1,4,5-trisphosphate receptors (IP3R) results from enormous amounts (1000 times greater than the amount needed to activate protein kinase A) of the second messenger cAMP produced by adenylyl cyclase (AC) molecules that are closely apposed to the IP3R channel. The authors were led to this unorthodox interpretation by their exploration of the mechanisms by which parathyroid hormone (PTH), which itself does not cause the release of calcium, enhanced the effects of other hormones on the release via IP3Rs of calcium from internal stores. Only PTH analogs that activated AC potentiated calcium release. High concentrations of cAMP analogs were sufficient to reproduce the effects of PTH and were not additive with the effects of the hormone. The authors propose that AC and IP3Rs are in such close proximity that activation of the cyclase produces a massive all-or-none response of the channel that is resistant to modulation by agents that alter cytoplasmic concentrations of cAMP; immunoprecipitation experiments confirmed the prediction that IP3Rs and AC were associated physically. Such signaling complexes would have on-off or switchlike properties and could allow graded responses by recruitment of more activated complexes rather than graded response at an individual complex. To add to the complexity, the IP3R-associated isoform of AC is inhibited by calcium. Thus, localized concentrations of cAMP and calcium might oscillate as a result of feedback inhibition. — LBR

J. Cell Biol. 183, 297 (2008).

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