Effect of luminal and extravesicular Ca2+ on NAADP binding and release properties

Bak, Judit; Billington, Richard; Genazzani, Armando A.

doi:10.1016/s0006-291x(02)00761-1

Cited by 12 publications

(7 citation statements)

References 27 publications

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“…TPC2 also exhibits a number of unusual gating characteristics that provide an underlying explanation for many of the peculiarities of NAADP-induced Ca 2+ release in cellular systems (9, 46) including extreme sensitivity to low concentrations of NAADP, inhibition by 1 μ m Ned-19 and by high [NAADP], and time-dependent NAADP actions (38). A key aspect of TPC2 regulation is that the sensitivity and reversibility of NAADP binding are controlled by the luminal pH and [Ca 2+ ].…”

Section: Discussionmentioning

confidence: 99%

TPC2 Is a Novel NAADP-sensitive Ca2+ Release Channel, Operating as a Dual Sensor of Luminal pH and Ca2+

Pitt

Funnell

Sitsapesan

et al. 2010

Journal of Biological Chemistry

208

266

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Nicotinic acid adenine dinucleotide phosphate (NAADP) is a molecule capable of initiating the release of intracellular Ca2+ required for many essential cellular processes. Recent evidence links two-pore channels (TPCs) with NAADP-induced release of Ca2+ from lysosome-like acidic organelles; however, there has been no direct demonstration that TPCs can act as NAADP-sensitive Ca2+ release channels. Controversial evidence also proposes ryanodine receptors as the primary target of NAADP. We show that TPC2, the major lysosomal targeted isoform, is a cation channel with selectivity for Ca2+ that will enable it to act as a Ca2+ release channel in the cellular environment. NAADP opens TPC2 channels in a concentration-dependent manner, binding to high affinity activation and low affinity inhibition sites. At the core of this process is the luminal environment of the channel. The sensitivity of TPC2 to NAADP is steeply dependent on the luminal [Ca2+] allowing extremely low levels of NAADP to open the channel. In parallel, luminal pH controls NAADP affinity for TPC2 by switching from reversible activation of TPC2 at low pH to irreversible activation at neutral pH. Further evidence earmarking TPCs as the likely pathway for NAADP-induced intracellular Ca2+ release is obtained from the use of Ned-19, the selective blocker of cellular NAADP-induced Ca2+ release. Ned-19 antagonizes NAADP-activation of TPC2 in a non-competitive manner at 1 μm but potentiates NAADP activation at nanomolar concentrations. This single-channel study provides a long awaited molecular basis for the peculiar mechanistic features of NAADP signaling and a framework for understanding how NAADP can mediate key physiological events.

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Section: Discussionmentioning

confidence: 99%

TPC2 Is a Novel NAADP-sensitive Ca2+ Release Channel, Operating as a Dual Sensor of Luminal pH and Ca2+

Pitt

Funnell

Sitsapesan

et al. 2010

Journal of Biological Chemistry

208

266

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“…luminal [Ca 2+ ]) modulates resident receptor channels in the store membrane has been with us for many years, applied first to RyRs and then later to IP 3 Rs [6,12]. Since then, other Ca 2+ homeostatic proteins have emerged that tailor their activity to the luminal Ca 2+ content such as SERCA [34] and STIM1 [35] and so the view that NAADP-regulated channels were, according to some criteria, insensitive to luminal Ca 2+ singled them out as unique [9]. Unfortunately, this study was flawed because it was not then known that NAADP targets acidic Ca 2+ stores and the luminal Ca 2+ was manipulated with ionomycin [9] which does not act at acidic Ca 2+ stores [36].…”

Section: Discussionmentioning

confidence: 99%

“…For IP 3 Rs and RyRs, higher luminal Ca 2+ concentrations promote channel opening, possibly via intermediate luminal Ca 2+ -binding proteins [5,6,12,13]. However, NAADP-regulated channels were initially reported to be insensitive to luminal Ca 2+ [9]. More recently, mammalian members of the TPC (two-pore channel) family – the newly discovered target of NAADP [14–16] – exhibited sensitivity to luminal Ca 2+ whereby increasing luminal Ca 2+ concentrations enhanced channel activity in lipid bilayers [17,18].…”

Section: Introductionmentioning

confidence: 99%

The luminal Ca2+ chelator, TPEN, inhibits NAADP-induced Ca2+ release

2012

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The regulation of Ca2+ release by luminal Ca2+ has been well studied for the ryanodine and IP3 receptors but has been less clear for the NAADP-regulated channel. In view of conflicting reports, we have re-examined the issue by manipulating luminal Ca2+ with the membrane-permeant, low affinity Ca2+ buffer, TPEN, and monitoring NAADP-induced Ca2+ release in sea urchin egg homogenate. NAADP-induced Ca2+ release was almost entirely blocked by TPEN (IC50 17–25 μM) which suppressed the maximal extent of Ca2+ release without altering NAADP sensitivity. In contrast, Ca2+ release via IP3 receptors was 3- to 30-fold less sensitive to TPEN whereas that evoked by ionomycin was essentially unaffected. The effect of TPEN on NAADP-induced Ca2+ release was not due to an increase in the luminal pH or chelation of trace metals since it could not be mimicked by NH4Cl or phenanthroline. The fact that TPEN had no effect upon ionophore-induced Ca2+ release also argued against a substantial reduction in the driving force for Ca2+ efflux. We propose that, in the sea urchin egg, luminal Ca2+ is important for gating native NAADP-regulated two-pore channels.

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“…Activation of phospholipase C by an increase in [Ca 2+ ] c (Biden et al 1987) or by depolarization alone (Gromada et al 1996; Liu et al 1996) may also explain indirect CICR and DICR. It is also worth noting that receptors for nicotinic acid‐adenine dinucleotide phosphate (NAADP) are insensitive to divalent cations and cannot trigger CICR (Chini & Dousa, 1996; Bak et al 1999; Bak et al 2002; Galione & Churchill, 2002).…”

mentioning

confidence: 99%

Atypical Ca²⁺‐induced Ca²⁺ release from a sarco‐endoplasmic reticulum Ca²⁺‐ATPase 3‐dependent Ca²⁺ pool in mouse pancreatic β‐cells

Beauvois¹,

Arredouani²,

Jonas³

et al. 2004

The Journal of Physiology

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Rs) because it was resistant to heparin. Nor did it involve ryanodine receptors (RyRs) because it persisted after blockade of RyRs with ryanodine, and was not mimicked by caffeine, a RyR agonist. Moreover, RyR1 and RyR2 mRNA were not found and RyR3 mRNA was only slightly expressed in purified β-cells. A CICR could also be detected in a limited number of cells in response to glucose. Our data demonstrate, for the first time in living cells, the existence of an atypical CICR that is independent from the IP 3 R and the RyR. This CICR is prominent in response to a supraphysiological stimulation with high K + , but plays little role in response to glucose in non-obese mouse pancreatic β-cells.

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Effect of luminal and extravesicular Ca2+ on NAADP binding and release properties

Cited by 12 publications

References 27 publications

TPC2 Is a Novel NAADP-sensitive Ca2+ Release Channel, Operating as a Dual Sensor of Luminal pH and Ca2+

TPC2 Is a Novel NAADP-sensitive Ca2+ Release Channel, Operating as a Dual Sensor of Luminal pH and Ca2+

The luminal Ca2+ chelator, TPEN, inhibits NAADP-induced Ca2+ release

Atypical Ca²⁺‐induced Ca²⁺ release from a sarco‐endoplasmic reticulum Ca²⁺‐ATPase 3‐dependent Ca²⁺ pool in mouse pancreatic β‐cells

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Effect of luminal and extravesicular Ca2+ on NAADP binding and release properties

Cited by 12 publications

References 27 publications

TPC2 Is a Novel NAADP-sensitive Ca2+ Release Channel, Operating as a Dual Sensor of Luminal pH and Ca2+

TPC2 Is a Novel NAADP-sensitive Ca2+ Release Channel, Operating as a Dual Sensor of Luminal pH and Ca2+

The luminal Ca2+ chelator, TPEN, inhibits NAADP-induced Ca2+ release

Atypical Ca2+‐induced Ca2+ release from a sarco‐endoplasmic reticulum Ca2+‐ATPase 3‐dependent Ca2+ pool in mouse pancreatic β‐cells

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Atypical Ca²⁺‐induced Ca²⁺ release from a sarco‐endoplasmic reticulum Ca²⁺‐ATPase 3‐dependent Ca²⁺ pool in mouse pancreatic β‐cells