Calcium signaling via two-pore channels: local or global, that is the question

Abstract

Recently, we identified, for the first time, two-pore channels (TPCs, TPCN for gene name) as a novel family of nicotinic acid adenine dinucleotide phosphate (NAADP)-gated, endolysosome-targeted calcium release channels. Significantly, three subtypes of TPCs have been characterized, TPC1-3, with each being targeted to discrete acidic calcium stores, namely lysosomes (TPC2) and endosomes (TPC1 and TPC3). That TPCs act as NAADP-gated calcium release channels is clear, given that NAADP binds to high- and low-affinity sites associated with TPC2 and thereby induces calcium release and homologous desensitization, as observed in the case of endogenous NAADP receptors. Moreover, NAADP-evoked calcium signals via TPC2 are ablated by short hairpin RNA knockdown of TPC2 and by depletion of acidic calcium stores with bafilomycin. Importantly, however, NAADP-evoked calcium signals were biphasic in nature, with an initial phase of calcium release from lysosomes via TPC2, being subsequently amplified by calcium-induced calcium release (CICR) from the endoplasmic reticulum (ER). In marked contrast, calcium release via endosome-targeted TPC1 induced only spatially restricted calcium signals that were not amplified by CICR from the ER. These findings provide new insights into the mechanisms that cells may utilize to “filter” calcium signals via junctional complexes to determine whether a given signal remains local or is converted into a propagating global signal. Essentially, endosomes and lysosomes represent vesicular calcium stores, quite unlike the ER network, and TPCs do not themselves support CICR or, therefore, propagating regenerative calcium waves. Thus “quantal” vesicular calcium release via TPCs must subsequently recruit inositol 1,4,5-trisphoshpate receptors and/or ryanodine receptors on the ER by CICR to evoke a propagating calcium wave. This may call for a revision of current views on the mechanisms of intracellular calcium signaling. The purpose of this review is, therefore, to provide an appropriate framework for future studies in this area.

Organelle-specific Subunit Interactions of the Vertebrate Two-pore Channel Family

“…These genes encode the two-pore channel family (TPC1-3), 4 of which TPC1 was first cloned in 2000 (2). Until recently, however, no functional activity had been determined, and the subcellular distribution of TPCs had not been defined until our proposal that TPC1-3 represent a novel family of endolysosome-targeted channels (1,3). The majority of our findings have since been confirmed by others (4 -8).…”

A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection

“…The [Ca 2 þ ]i is maintained at a low level under basal conditions, with increases triggering a variety of cellular responses including gene expression and the release of humoral factors 51,52 . In most instances, increases in [Ca 2 þ ]i occur in the form of oscillations, which are maintained by a sustained increase in .…”

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).…”