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Bidirectional Ca2+ Signaling Occurs Between the Endoplasmic Reticulum and Acidic Organelles

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Bidirectional Ca2+ Signaling Occurs Between the Endoplasmic Reticulum and Acidic Organelles JCB: Article Bidirectional Ca2+ signaling occurs between the endoplasmic reticulum and acidic organelles Anthony J. Morgan, Lianne C. Davis, Siegfried K.T.Y. Wagner, Alexander M. Lewis, John Parrington, Grant C. Churchill, and Antony Galione Department of Pharmacology, University of Oxford, Oxford OX1 3QT, England, UK he endoplasmic reticulum (ER) and acidic organelles activate the NAADP pathway in two ways: first, by stim- (endo-lysosomes) act as separate Ca2+ stores that ulating Ca2+-dependent NAADP synthesis; second, by T release Ca2+ in response to the second messengers activating NAADP-regulated channels. Moreover, the IP3 and cADPR (ER) or NAADP (acidic organelles). Typi- differential effects of EGTA and BAPTA (slow and fast cally, trigger Ca2+ released from acidic organelles by Ca2+ chelators, respectively) suggest that the acidic or- NAADP subsequently recruits IP3 or ryanodine receptors ganelles are preferentially activated by local microdo- on the ER, an anterograde signal important for amplifi- mains of high Ca2+ at junctions between the ER and cation and Ca2+ oscillations/waves. We therefore in­ acidic organelles. Bidirectional organelle communica- vestigated whether the ER can signal back to acidic tion may have wider implications for endo-lysosomal organelles, using organelle pH as a reporter of NAADP function as well as the generation of Ca2+ oscillations action. We show that Ca2+ released from the ER can and waves. Introduction A universal signal transduction mechanism for extracellular 2009, 2010a; Calcraft et al., 2009; Zong et al., 2009; Ruas et al., stimuli is the release of Ca2+ from intracellular stores (Berridge 2010; Morgan et al., 2011; Davis et al., 2012). et al., 2003) with stimulus-specific Ca2+ patterns fine-tuned by To date, the cross talk (“channel chatter”; Patel et al., 2001) 2+ appropriate combinations of three Ca -mobilizing intracellular between the NAADP and IP3/cADPR pathways has centered messengers: D-myo-inositol 1,4,5-trisphosphate (IP3), cyclic upon “anterograde” signaling from the acidic stores to the ER in ADP-ribose (cADPR), and nicotinic acid adenine dinucleotide the “trigger” hypothesis (or two-pool model; Churchill and phosphate (NAADP; Cancela et al., 2002; Morgan and Galione, Galione, 2001): NAADP activates TPCs on acidic stores to pro- 2008). Thus, multiple messengers entrain Ca2+ oscillations and vide the critical “pacemaker” trigger Ca2+ that is subsequently THE JOURNAL OF CELL BIOLOGY waves, e.g., at fertilization (Churchill and Galione, 2001; Santella amplified by IP3 receptors (IP3Rs) and/or ryanodine receptors et al., 2004; Moccia et al., 2006; Whitaker, 2006; Davis et al., (RyRs) on the neutral ER/SR (Morgan et al., 2011), either via 2008), the activation of T cells (Steen et al., 2007; Davis et al., Ca2+-induced Ca2+ release (CICR; Patel et al., 2001; Kinnear 2012) or pancreatic acinar cells (Cancela et al., 2002; Yamasaki et al., 2004; Zong et al., 2009; Brailoiu et al., 2010b; Ruas et al., et al., 2004). 2010; Davis et al., 2012) or by luminal priming (Churchill and While IP3 and cADPR target their cognate receptors on Galione, 2001; Macgregor et al., 2007). the neutral sarcoplasmic or endoplasmic reticulum (SR/ER), It is unknown whether Ca2+ signals travel in the reverse NAADP evokes Ca2+ release from acidic Ca2+ stores (Churchill direction from ER to the acidic Ca2+ stores to make channel et al., 2002; Morgan et al., 2011), probably by activating com- chatter a two-way conversation that might be important for re- plexes of the two-pore channel (TPC) family (E. Brailoiu et al., generative cycles of Ca2+ oscillations and waves. Consequently, we have investigated whether ER (IP3/cADPR) signals com- municate with acidic Ca2+ stores (NAADP) by using a novel Correspondence to Anthony J. Morgan: [email protected]; or Antony Galione: [email protected] © 2013 Morgan et al. This article is distributed under the terms of an Attribution– Abbreviations used in this paper: cADPR, cyclic ADP-ribose; CPA, cyclopiazonic Noncommercial–Share Alike–No Mirror Sites license for the first six months after the pub- acid; IP3, inositol 1,4,5-trisphosphate; NAADP, nicotinic acid adenine dinucleo- lication date (see http://www.rupress.org/terms). After six months it is available under a tide phosphate; pHL, luminal pH; RyR, ryanodine receptor; SERCA, sarcoendo- Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, plasmic reticulum Ca2+ ATPase; TPC, two-pore channel. as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). The Rockefeller University Press $30.00 J. Cell Biol. Vol. 200 No. 6 789–805 www.jcb.org/cgi/doi/10.1083/jcb.201204078 JCB 789 single-cell approach for monitoring acidic store activation. The concentration (Fig. 1 C). Indeed, when the magnitude of the re- activation of acidic Ca2+ stores is difficult to extract from cyto- sponses was normalized to the maximum response, there was no solic Ca2+ recordings that are the net result of multiple processes. difference in the sensitivity of the two regions, only in their dy- This issue can be offset by monitoring the organelle lumen it- namic range (Fig. 1 D). Consequently, the ratio of the responses self using optical reporters, e.g., targeted to ER, mitochondria, in the periphery and center is almost invariant with NAADP and secretory granules (Arnaudeau et al., 2001; Pinton et al., concentration (the center being 30% of the periphery; Fig. 1 E). 2007; Santodomingo et al., 2008). By analogy, we have moni- Kinetically, the maximal pHLash response (at 70% UV) oc- 2+ tored the luminal pH (pHL) of acidic Ca stores as a readout curred with a time to peak of 6.4 ± 0.4 s and a lag of 3.2 ± 0.3 s of activation because a prompt alkalinization accompanies (n = 14). Such response times are congruent with other second NAADP-induced Ca2+ release in sea urchin eggs (Morgan and messenger reporters (Nikolaev et al., 2004). Galione, 2007a,b; Morgan, 2011), pancreatic acinar cells (Cosker To address spatial fidelity, we focally uncaged NAADP at et al., 2010), and atrial myocytes (Collins et al., 2011). one pole of the egg (Fig. 1, F–H). In the majority of eggs (n = 22), Hence, we have investigated sea urchin eggs where the the pHL response precisely overlapped with the site of expo- sperm stimulus couples to NAADP, cADPR, and IP3 (Morgan, sure to UV and remained at the site until it waned (Fig. 1, F–H; 2011). Given that, of these three, NAADP is unique in changing Fig. S1). This indicated that neither the diffusion of NAADP nor acidic store pHL in egg homogenate and that these stores are of the target vesicles themselves were confounding factors over well distributed throughout the sea urchin egg (Lee and Epel, this period. Thus, pHL faithfully mapped experimental increases 1983; Churchill et al., 2002; Morgan and Galione, 2007a,b; in cytosolic NAADP and acidic store activation. However, in a Ramos et al., 2010), we have imaged Ca2+ store alkalinization minority of eggs (n = 6) the initial, polarized response did even- to “map” where and when acidic stores are activated during a tually propagate to the antipode after remaining stationary at the physiological stimulus. Our results suggest that the ER and acidic UV site for 19 ± 3 s (Fig. S1 F). This regenerative phase clearly vesicles are in close apposition and that Ca2+ released from the required positive feedback and probably reflects the secondary 2+ ER by IP3/cADPR stimulates the NAADP pathway in an un- Ca oscillations and waves that can be entrained by uncaging expected retrograde manner, thereby amplifying acidic Ca2+ NAADP (Lee et al., 1997; Churchill and Galione, 2000, 2001). store signaling. This may have profound implications for Ca2+ oscillations and waves in all systems. Effect of NAADP antagonists on pHL If pHL is a faithful reporter of the NAADP/TPC pathway, then Results responses should be inhibited by NAADP antagonists. There- fore, we tested several antagonists with the fertilization-induced 2+ Ca release evoked by NAADP or fertilization is accompanied pHLash. Note that at fertilization, the pHL of acidic vesicles 2+ by a rapid increase in the pHL of acidic Ca stores (Morgan and changes differently in different regions of the egg: the periph- Galione, 2007a,b). In the intact sea urchin egg, this predomi- ery shows a prompt alkalinization (the pHLash) that accompa- 2+ nantly cortical pHL response was termed a pHLash (pronounced nies the main Ca wave and can be mimicked by NAADP “flash”) that was independent of cytosolic pH changes and exo- (Morgan and Galione, 2007a), whereas the center shows a slow cytosis (Morgan and Galione, 2007a). Because NAADP is unique acidification that is driven by an unrelated mechanism depen- + in evoking this pHL change (Morgan and Galione, 2007b), we dent upon extracellular Na (Lee and Epel, 1983; Morgan and exploited this as a “reporter” of acidic store activation (i.e., Galione, 2007a). NAADP-induced Ca2+ release), first testing its sensitivity and We first tested the fluorescent NAADP receptor antago- spatiotemporal fidelity. nist, Ned-19 (Fig. S2; Naylor et al., 2009; Barceló-Torns et al., 2011). Preincubation of eggs with Ned-19 resulted in a concen- Characterizing responses to photolysis tration-dependent increase in Ned-19 loading, as assessed by its of caged NAADP intrinsic fluorescence Fig.( 2 C), but which did not affect the We photo-released NAADP from its microinjected caged pre- resting pHL (% control, 80 µM, 95 ± 2; 160 µM, 105 ± 3; P > 2+ cursor using a UV laser. No pHL (or Ca ) responses to UV light 0.05, n = 47–83). In keeping with a role for NAADP, Ned-19 were observed in the absence of caged NAADP (ratio: 0.03 ± inhibited the sperm-induced pHLash (Fig. 2, A–C).
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