Editors' ChoiceCalcium signaling

Can You Hear Me Now?

Science Signaling  28 Oct 2008:
Vol. 1, Issue 43, pp. ec368
DOI: 10.1126/scisignal.143ec368

It’s a bit like talking to your neighbor at a dinner party with a megaphone, but Tovey et al. report that stimulation of calcium release by inositol 1,4,5-trisphosphate receptors (IP3Rs) results from enormous amounts [1000 times greater than the amount in the cytoplasm that activates protein kinase A (PKA)] of the second messenger adenosine 3′,5′-monophosphate (cAMP) produced by adenylyl cyclase (AC) molecules closely apposed to the IP3R channel in cell membranes. The authors were forced to this unorthodox interpretation by results of their exploration of the mechanisms by which parathyroid hormone (PTH), which itself does not cause release of calcium, could enhance the effects of other hormones on release of calcium though IP3Rs. 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. Various methods used to inhibit the most common target of cAMP, PKA, showed that that enzyme was not required. Furthermore, inhibiting global concentrations of cAMP in the cell also did not affect the action of PTH on calcium release. The authors could only explain these seemingly contradictory experiments by proposing that AC and IP3Rs were operating in such close proximity that activation of the cyclase produced a massive all-or-none response of the channel that was resistant to modulation by agents that changed overall concentrations of cAMP in the cell. Immunoprecipitation experiments confirmed the prediction that IP3Rs and AC were associated in cells. Another prediction of the authors’ model was that partial inhibition of AC in all complexes in the cell would be less effective than complete inhibition at a subset of the IP3R-AC complexes. Indeed, uniform inhibition of AC with pharmacological inhibitors did not inhibit calcium signaling, but depletion of AC6 with small interfering RNA (which inhibited cellular concentrations of cAMP to about the same extent, ~70%, as did the inhibitor) did reduce calcium release. The authors thus conclude that IP3R or a closely associated protein is a direct target of low-affinity binding by cAMP. 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, AC6 is inhibited by calcium. Thus, the authors note that localized concentrations of cAMP and calcium might oscillate as a result of feedback inhibition, as they can also do in whole cells.

S. C. Tovey, S. G. Dedos, E. J. A. Taylor, J. E. Church, C. W. Taylor, Selective coupling of type 6 adenylyl cyclase with type 2 IP3 receptors mediates direct sensitization of IP3 receptors by cAMP. J. Cell Biol. 183, 297-311 (2008). [Abstract] [Full Text]