The recent discovery of nicastrin as a partner for presenilin highlighted once again the putative proteolytic role of this protein and its identity as γ-secretase. However, there seems to be more to the role of the presenilins than just cleaving the amyloid precursor and other membrane proteins. For example, presenilins can affect calcium homeostasis, presumably by potentiating the inositol-1,4,5-trisphosphate (Ins(1,4,5)P3)-mediated Ca2+ release from intracellular stores. Yoo et al. have tried to gain further insight into the actions of the presenilins on calcium dynamics by focusing on a process tightly linked to Ca2+ release from intracellular pools — capacitive calcium entry (CCE).

Figure adapted from Berridge, M. J. et al. Nature Rev. Mol. Cell Biol. 1, 11–21 (2000).

When intracellular stores release their calcium contents, CCE takes place through plasma membrane channels presumably activated by the Ins(1,4,5)P3 receptor itself. This extra intracellular calcium is then used to replenish the stores. Yoo et al. found that CCE (and no other routes of calcium influx) is modulated by the presenilins. In the absence of presenilin-1, or in the presence of an inactive form of this protein, CCE was enhanced in cultured neurons. Conversely, presenilin mutants that increase the production of the amyloidogenic peptide Aβ42, attenuated CCE. Furthermore, the putative CCE-associated current ICRAC was also reduced in the presence of the `gain-of-function' mutant presenilins.

An intriguing finding in this study was the fact that blocking CCE by pharmacological means increased the production of Aβ42, an effect dependent on the presence of a functional presenilin-1. However, increasing Aβ42 by other manipulations did not lead to a reciprocal change on CCE amplitude. These observations indicate that the modulation of CCE by the presenilins may be an event upstream of γ-secretase activity, pointing to this route of calcium influx as a possible target for therapeutic approaches against Alzheimer's disease.

It will be important to establish the actual mechanism whereby presenilins affect CCE. Do they modulate calcium entry by proteolysis of a modulatory element? If this were the case, it would expand the list of molecules susceptible to the action of the presenilins and it would point to a more general role for these molecules in the metabolism of membrane proteins.