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

Abstract

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 endolysosomal 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.

Intracellular angiotensin II activates rat myometrium

“…Intracellular organelles reportedly involved in Ca 2ϩ release include the endoplasmic reticulum (ER) and acidic Ca 2ϩ stores such as lysosomes (3,36). Nicotinic acid-adenine dinucleotide phosphate (NAADP) is a second messenger that releases Ca 2ϩ from lysosomes (25,36). Pretreatement with Ned-19, an inhibitor of NAADP signaling (35) did not affect angiotensin II-induced Ca 2ϩ response.…”

“…In the absence of extracellular Ca 2ϩ , the response to angiotensin II is only slightly decreased indicating a major involvement of Ca 2ϩ release from internal stores. Intracellular organelles reportedly involved in Ca 2ϩ release include the endoplasmic reticulum (ER) and acidic Ca 2ϩ stores such as lysosomes (3,36). Nicotinic acid-adenine dinucleotide phosphate (NAADP) is a second messenger that releases Ca 2ϩ from lysosomes (25,36).…”

IP3 Receptors: Toward Understanding Their Activation

“…Very recently, a third family of intracellular Ca 2þ channels, unrelated to RyR and IP 3 R, has been implicated in Ca 2þ signaling. These are the two-pore channels (TPC) that are activated by NAADP and release Ca 2þ from acidic Ca 2þ stores, including lysosomes and endosomes (Patel et al 2010;Zhu et al 2010). Several trp (transient receptor protein) channels, in addition to their roles in the plasma membrane, may also mediate release of Ca 2þ from intracellular stores (Gees et al 2010).…”

Intracellular Endothelin Type B Receptor-driven Ca2+ Signal Elicits Nitric Oxide Production in Endothelial Cells

“…Indeed, activation of lysosomal ET B receptors occurred readily in response to microinjected ET- influx, is the main mechanism underlying the ET-1-induced effect. The response to ET-1 was not affected by preventing lysosomal Ca 2ϩ release with the two-pore channel blocker Ned-19 (28,49); thus, despite their localization, activation of ET B receptors does not mobilize Ca 2ϩ via two-pore channel activation. Conversely, the effect of intracellular ET-1 was sensitive to IP 3 R but not ryanodine receptor blockade, pointing to the IP 3 -responsive stores as the major Ca 2ϩ pool mobilized upon activation of lysosomal ET B .…”