Multiple isoforms of the ryanodine receptor are expressed in rat pancreatic acinar cells

Fitzsimmons, Timothy J.; Gukovsky, Ilya; McRoberts, James A.; RODRIGUEZ, Edward; Lai, F. Anthony; Pandol, Stephen J.

doi:10.1042/bj3510265

Cited by 41 publications

(9 citation statements)

References 27 publications

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“…This same study also demonstrated receptor specificity for the production of NAADP and cADPR, whereby increases in cADPR levels via stimulation of acetylcholine muscarinic receptors as well as cholecystokinin A receptors, whereas NAADP increased only through the activation of cholecystokinin A. Intriguingly, the striking difference seen in time courses between NAADP and cADPR production, where the increase in NAADP was rapid and transient, whereas the increase in cADPR was much prolonged, strongly supports the proposed hypothesis that NAADP provides a localized Ca 2+ trigger signal at the apical region where InsP 3 Rs, RyRs and NAADP‐sensitive Ca 2+ stores coexist [45,56–62](Fig. 4), and subsequently this localized Ca 2+ signal is amplified by a CICR mechanism via sensitization of RyRs throughout of the cell [20,38,39,50–52,60–63]. Cell surface receptors are predominantly located in the basolateral membrane, however, agonist‐induced Ca 2+ signals initiate at the apical pole before propagating into the basolateral domain by the CICR mechanism.…”

Section: Changes In Endogenous Levels Of Naadpsupporting

confidence: 68%

Calcium signalling by nicotinic acid adenine dinucleotide phosphate (NAADP)

2005

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Intracellular Ca2+ signals are coordinated to elicit spatiotemporal patterns. These include repetitive Ca 2+ transients, which may be localized or propagated as regenerative waves that may also pass into neighbouring cells [1][2][3]. d-myo-Inositol 1,4,5-trisphosphate (InsP 3 ) is a well-established intracellular Ca 2+ mobilizing messenger in many cell types [3], and is a paradigm for additional molecules that release Ca 2+ from intracellular Ca 2+ stores. Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) were first discovered in the sea urchin egg as novel Ca 2+ mobilizing agents [4][5][6]. In this cell, cADPR was shown to target ryanodine receptors (RyRs) to release Ca 2+ from the endoplasmic reticulum (ER), and now has been established as an intracellular messenger in several cell types [7,8]. In contrast, NAADP was found to activate a Ca 2+ release mechanism distinct from those activated by InsP 3 and cADPR, based on pharmacology and self-induced inactivation of the different Ca 2+ release mechanisms. It has thus been of great interest to investigate the physiology, enzymology and pharmacology of the NAADP signalling pathway. Recent reports have shown increases in NAADP levels in response to cellular stimuli fulfilling a major criterion for the classification of NAADP as a second messenger not only in sea urchin eggs but also in mammalian cells [9][10][11][12]. Here we focus on the Ca 2+ mobilizing properties of NAADP and compare them with the actions of InsP 3 and cADPR. Distinct properties of NAADPSince the discovery of NAADP as a Ca 2+ mobilizing molecule in sea urchin egg homogenates, the sea urchin egg has remained an important system in which to study the actions of NAADP. NAADP has an ability to release Ca 2+ from intracellular Ca 2+ stores and is the most potent Ca 2+ mobilizing agent described so [14,21,29]. Therefore in contrast to [43]. A second model, the two pool or trigger hypothesis, is based on the idea that there is a distinct NAADP-sensitive storage organelle, possibly an thapsigargin-insensitive acidic store [28], that is responsible for a localized signal which is amplified by InsP 3 Rs and RyRs the on the ER by CICR [22,34,36,38]. This model accounts for the finding in some cells that localized NAADP-induced signals persist in the presence of InsP 3 Rs and RyR antagonists or thapsigargin, but are abolished by agents that dissipate storage of by acidic organelles, such as the vacuolar H + pump inhibitor, bafilomycin A1. This has been most clearly demonstrated in the sea urchin egg [28], but also extended to several mammalian cell types [11,[44][45][46]. Two types of pharmacological manipulation of acidic stores have been investigated with regard to NAADP-evoked release. Glycyl-phenylalanyl-naphthylamide (GPN) is an agent that penetrates cellular membranes but is a substrate for the luminal lysosomal enzyme cathepsin C trapping membrane impermeant products within lysosomes resulting in disruption of lysosomal-related organelles by osmotic lysis [47]. T...

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Section: Changes In Endogenous Levels Of Naadpsupporting

confidence: 68%

Calcium signalling by nicotinic acid adenine dinucleotide phosphate (NAADP)

2005

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“…RYR-dependent Ca 2ϩ release in the basolateral region of the pancreatic acinar cell modulates pathological intra-acinar protease activation that overlaps with the RYR in a nonapical, supranuclear region. Although we and others have shown this in rat acinar cells (14,25), our present in vivo studies used mice. Nevertheless, mouse acinar cells appear to exhibit similar properties in RYR-Ca 2ϩ signaling as rat acinar cells.…”

Section: Resultsmentioning

confidence: 52%

“…Of the three RYR isoforms, RYR1 was expressed in mouse acinar cells. By contrast, in rat acinar cells one study showed expression of RYR2 (34) and another demonstrated all three isoforms (14). Thus species-specific expression patterns of the RYR isoforms will need to be examined when translating our findings to humans.…”

Section: Discussionmentioning

confidence: 91%

Dantrolene mitigates caerulein-induced pancreatitis in vivo in mice

Orabi¹,

Shah²,

Ahmad³

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Acute pancreatitis is a painful, inflammatory disorder for which adequate treatments are lacking. An early, critical step in its development is the aberrant signaling of Ca(2+) within the pancreatic acinar cell. This Ca(2+) release is modulated by the intracellular Ca(2+) channel the ryanodine receptor (RYR). We have previously shown that RYR inhibition reduces pathological intra-acinar protease activation, an early marker of pancreatitis. In this study, we examined whether pretreatment with the RYR inhibitor dantrolene attenuates the severity of caerulein-induced pancreatitis in mice. Immunofluorescent labeling for RYR from mouse pancreatic sections showed localization to the basolateral region of the acinar cell. After 1 h of caerulein hyperstimulation in vivo, dantrolene 1) reduced pancreatic trypsin activity by 59% (P < 0.05) and 2) mitigated early ultrastructural derangements within the acinar cell. Eight hours after pancreatitis induction, dantrolene reduced pancreatic trypsin activity and serum amylase by 61 and 32%, respectively (P < 0.05). At this later time point, overall histological severity of pancreatitis was reduced by 63% with dantrolene pretreatment (P < 0.05). TUNEL-positive cells were reduced by 58% (P < 0.05). These data suggest that the RYR plays an important role in mediating early acinar cell events during in vivo pancreatitis and contributes to disease severity. Blockade of Ca(2+) signals and particularly RYR-Ca(2+) may be useful as prophylactic treatment for this disease in high-risk settings for pancreatitis.

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“…To confirm these findings, we isolated mRNA from mouse taste buds that had been harvested from circumvallate and foliate taste papillae for RT‐PCR analysis. Specific PCR primer pairs for all three RyR isoforms 1, 2 and 3 (Fitzsimmons et al. , 2000) were used to amplify PCR products.…”

Section: Resultsmentioning

confidence: 99%

“…The identity of all PCR products was confirmed by DNA sequencing. Previously published primers which cross at least one intron were used for the detection of mRNA encoding for the ryanodine isoforms (Fitzsimmons et al. , 2000).…”

Section: Methodsmentioning

confidence: 99%

Ryanodine receptors selectively contribute to the formation of taste‐evoked calcium signals in mouse taste cells

Rebello

Medler

2010

Eur J of Neuroscience

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The peripheral taste system uses multiple signaling pathways to transduce a stimulus into an output signal that activates afferent neurons. All of these signaling pathways depend on transient increases in intracellular calcium but the current understanding of these calcium signals is not well-developed. Using molecular and physiological techniques, this study establishes that ryanodine receptors (RyRs), specifically isoform 1, are expressed in taste cells and that their physiological function differs among cell types employing different signaling pathways. RyR1 contributes to some taste-evoked signals that rely on calcium release from internal stores but can also supplement the calcium signal that is initiated by opening VGCCs. In taste cells expressing both signaling pathways, RyR1 contributes to the depolarization-induced calcium signal but not to the calcium signal that depends on calcium release from stores. These data suggest that RyR1 is an important regulator of calcium signaling and that its physiological role in taste cells is dictated by the nature of the calcium signaling mechanisms expressed. Keywords taste cells; ryanodine receptors; calcium imaging; CICR; voltage gated calcium channelsThe sense of taste provides an organism with the ability to identify potential nutrients for consumption as well as the ability to detect and thus, avoid potentially harmful compounds. The peripheral taste system is comprised of taste receptor cells which are housed in taste buds and detect chemicals in the oral cavity. Ionic taste stimuli, which include salty and sour, interact directly with ion channels on taste cells while more chemically complex tastants (bitter, sweet, and umami stimuli) are detected by G protein-coupled receptors (GPCRs). Even though ionic and chemically complex stimuli activate distinct signaling pathways, both stimulus types utilize cytosolic calcium increases to cause neurotransmitter release. Sour stimuli rely on the activation of voltage-gated calcium channels (VGCCs) (Richter et al., 2003) to stimulate neurotransmitter release via chemical synapses while taste-activated GPCRs initiate a second messenger cascade that causes calcium release from internal stores (Akabas et al., 1988). These taste cells lack VGCCs and chemical synapses but elevate cytosolic calcium to mediate neurotransmitter release through a hemichannel (Huang et al., 2007;Romanov et al., 2007;Dando & Roper, 2009). Therefore, regardless of the signaling mechanism used by the cell, calcium is a critical second messenger in taste transduction, making its release and regulation by taste cells essential for normal signaling to occur. Earlier studies established that chemically complex taste stimuli activate the phospholipase Cβ 2/IP 3 receptor 3 (PLCβ 2/IP 3 R3) signaling pathway (Zhang et al., 2003;Zhao et al., 2003). However, behavioral studies using PLCβ 2-knockout mice found reduced but not abolished responses to bitter tastants (Dotson et al., 2005) indicating that the PLCβ 2 pathway is not solely responsible for tr...

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Multiple isoforms of the ryanodine receptor are expressed in rat pancreatic acinar cells

Cited by 41 publications

References 27 publications

Calcium signalling by nicotinic acid adenine dinucleotide phosphate (NAADP)

Calcium signalling by nicotinic acid adenine dinucleotide phosphate (NAADP)

Dantrolene mitigates caerulein-induced pancreatitis in vivo in mice

Ryanodine receptors selectively contribute to the formation of taste‐evoked calcium signals in mouse taste cells

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