Two-pore channels: Regulation by NAADP and customized roles in triggering calcium signals

Sandip Patel, Jonathan S. Marchant, Eugen Brailoiu

Research output: Contribution to journalReview articlepeer-review

67 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)480-490
Number of pages11
JournalCell Calcium
Issue number6
StatePublished - Jun 2010

Bibliographical note

Funding 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.

Copyright 2017 Elsevier B.V., All rights reserved.


  • Calcium
  • Calcium stores
  • Endosome
  • Lysosome
  • Two-pore channels


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