NAADP is a potent regulator of cytosolic calcium levels. Much evidence suggests that NAADP activates a novel channel located on an acidic (lysosomal-like) calcium store, the mobilisation of which results in further calcium release from the endoplasmic reticulum. Here, we discuss the recent identification of a family of poorly characterized ion channels (the two-pore channels) as endo-lysosomal NAADP receptors. The generation of calcium signals by these channels is likened to those evoked by depolarisation during excitation-contraction coupling in muscle. We discuss the idea that two-pore channels can mediate a trigger release of calcium which is then amplified by calcium-induced calcium release from the endoplasmic reticulum. This is similar to the activation of voltage-sensitive calcium channels and subsequent mobilisation of sarcoplasmic reticulum calcium stores in cardiac tissue. We suggest that two-pore channels may physically interact with ryanodine receptors to account for more direct release of calcium from the endoplasmic reticulum in analogy with the conformational coupling of voltage-sensitive calcium channels and ryanodine receptors in skeletal muscle. Interaction of two-pore channels with other calcium release channels likely occurs between stores " trans-chatter" and possibly within the same store " cis-chatter" We also speculate that trafficking of two-pore channels through the endo-lysosomal system facilitates interactions with calcium entry channels. Strategic placing of two-pore channels thus provides a versatile means of generating spatiotemporally complex cellular calcium signals.
Bibliographical noteFunding Information:
This work was supported by grants from the Biotechnology and Biological Sciences Research Council ( BB/G013721/1 ), Research in to Ageing and the Alzheimer's Research Trust (to SP) and the National Institutes of Health ( GM088790 to JSM and HL090804 to EB). We thank Dev Churamani, George Dickinson, Robert Hooper, Chi Li, Latha Ramakrishnan and Colin Taylor for useful discussions.
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- Calcium stores
- Two-pore channels