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Biological Research

versión impresa ISSN 0716-9760

Biol. Res. v.37 n.4 Santiago  2004 


Biol Res 37: 661-664, 2004


Local and global Ca2+ signals: physiology and pathophysiology


MRC Secretory Control Research Group, The Physiological Laboratory, University of Liverpool, Liverpool L69 3BX, UK


The pancreatic acinar unit is a classical example of a polarized tissue. Even in isolation, these cells retain their polarity, and this has made them particularly useful for Ca2+ signaling studies. In 1990, we discovered that this cell has the capability of producing both local cytosolic and global Ca2+ signals. The mechanisms underlying this signal generation have now been established. Furthermore, it has become clear that the local signals are sufficient for the control of both fluid and enzyme secretion, whereas prolonged global signals are dangerous and give rise to acute pancreatitis, a disease where the pancreas digests itself.

Key words: Pancreatic Acinar Cell, Intracellular Communication, Ca2+ Signal Compartmentalization, Ca2+ Release Mechanisms, Local Ca2+ Signals.

Dirección para Correspondencia


More than 30 years ago, it was shown that neurotransmitters eliciting fluid and enzyme secretion from exocrine glands activate the acinar cells by releasing Ca2+ into the cytosol from a store in the endoplasmic reticulum (ER) (Nielsen & Petersen, 1972). Twenty years ago work on pancreatic acinar cells by Irene Schulz, Michael Berridge and their collaborators (Streb et al., 1983) provided the original evidence for the Ca2+ releasing action of inositol 1,4,5-trisphosphate (IP3). Ironically, further work on the pancreatic acinar cells presented some problems for the general view that IP3 acts on the ER, since the primary intracellular Ca2+ release site turned out to be in the apical pole, which contains the secretory granules, but little ER (Thorn et al., 1993). It is now clear that all cytosolic Ca2+ signals elicited by neurotransmitter or hormone stimulation are initiated in the apical secretory granule area and in many cases are confined to this region (Petersen et al., 1994). These local apical Ca2+ signals control not only exocytosis (Park et al., 2004), but also acinar fluid secretion via regulation of Ca2+-activated Cl- channels specifically located in the apical plasma membrane (Park et al., 2001). This short review explains how the acinar cells manage to generate these local apical Ca2+ signals, which are crucial for their physiological function.


It is now well established that G-protein coupled receptors in many cases activate phospholipase C causing breakdown of membrane-bound phosphatidyl inositol bisphosphate (PIP2) resulting in the formation of inositol trisphosphate (IP3) and diacyl glycerol. It is possible to visualize the breakdown of PIP2 and formation of IP3 in real time in single cells by fluorescence measurements of the translocation of the GFP-conjugated PH domain of PLC. Such studies demonstrate clearly the breakdown of PIP2 in the basolateral membrane and the appearance of IP3 in the cytosol in response to ACh stimulation (Ashby et al., 2002).

Long distance communication between muscarinic receptors and intracellular Ca2+ release channels was revealed by carbachol uncaging in a patch pipette attached to the basal membrane and monitoring of the cytosolic Ca2+ concentration. These studies clearly showed that local stimulation of receptors at the base gave rise to Ca2+ signals at the other side of the cells in the apical (granular) pole. With strong stimulation, such Ca2+ signals would spread as a wave from the apex to the base (Ashby et al., 2003).


Osipchuk et al. (1990) discovered that acinar cells can produce local or global cytosolic Ca2+ signals, depending on the intensity of agonist stimulation. Flooding the cell interior with IP3 causes local Ca2+ spiking, specifically in the apical pole (Thorn et al., 1993). The same is true when using the more novel Ca2+ releasing messengers cyclic ADP-ribose (cADPR) or nicotinic acid adenine dinucleotide phosphate (NAADP) (Cancela et al., 2002). It is now clear that the specific localization of mitochondria on the border between the granular pole and the basolateral part of the cell surrounding the nucleus is crucial for confining Ca2+ signals initiated in the apical pole to that region (Tinel et al., 1999). When all three intracellular messengers are put together, there is marked potentiation resulting in global Ca2+ signals progressing as waves from the apical pole to the base of the cells (Cancela et al., 2002).


We have recently mapped the Ca2+-sensitive Ca2+ release sites from the endoplasmic reticulum in pancreatic acinar cells using local uncaging of caged Ca2+ and have shown that Ca2+-induced Ca2+ release (which does not involve IP3 formation) can only be triggered in the apical pole and is dependent upon both functional IP3 and ryanodine receptors (Ashby et al., 2002). Ryanodine itself can trigger Ca2+ waves, which always start in the apical pole.

A detailed investigation of the distribution of ER in living acinar cells using a number of different ER-specific fluorescent probes in conjunction with confocal and two-photon microscopy shows that although the bulk of the ER is clearly located in the basolateral part of the cells, there is significant invasion of ER into the granular pole and each secretory granule is surrounded by strands of ER (Gerasimenko et al., 2002). These data provide the framework for a coherent and internally consistent theory for cytosolic Ca2+ signal generation in the secretory pole, where the primary Ca2+ release occurs from ER terminals in the apical pole supplied with Ca2+ from the main store at the base of the cell via the tunnel function of the ER (Petersen et al., 2001).


Recent work has defined the mechanism of action of NAADP on isolated nuclei from pancreatic acinar cells. Ca2+ release from the envelope of these nuclei could be activated by NAADP as well as by IP3 and cADPR. Each of these agents reduced the Ca2+ concentration inside the nuclear envelope and this was associated with a transient rise in the nucleoplasmic Ca2+ concentration. NAADP released Ca2+ from the same thapsigargin-sensitive pool as IP3 and cADPR. The NAADP action was specific since, for example, NADP was ineffective. The Ca2+ release was unaffected by procedures interfering with acidic organelles (bafilomycin, brefeldin, nigericin). Ryanodine blocked the Ca2+ releasing effects of NAADP, cADPR and caffeine, but not IP3. Ruthenium red also blocked the Ca2+ release elicited by NAADP but not by IP3. IP3 receptor blockade did not inhibit the Ca2+ release elicited by NAADP or cADPR.

We conclude that the nuclear envelope/endoplasmic reticulum contains both functional ryanodine and IP3 receptors, which can be activated separately and independently: the ryanodine receptors by either NAADP or cADPR and the IP3 receptors by IP3. These data are most easily understood by assuming that the NAADP receptor is not itself an ion channel. The characteristics of NAADP- and cADPR-elicited Ca2+ release from the nuclear envelope are essentially identical except that cADPR can still act to release Ca2+ normally when the NAADP receptors have been inactivated by a high NAADP concentration. The simplest explanation is that occupied cADPR and NAADP receptors can both interact with ryanodine receptors to increase their open state probability (Gerasimenko et al., 2003).


Hyperstimulation of acinar cells evokes sustained global Ca2+ signals, which are associated with trypsin activation in the secretory granules and transformation of the normally electron dense granules into vacuoles (Raraty et al., 2000). It was later shown that bile acids implicated in the generation of pancreatitis also have the ability to generate prolonged global Ca2+ signals (Voronina et al., 2002).

A recent study dealing with the actions of alcohol and alcohol metabolites on Ca2+ transports in pancreatic acinar cells shows that whereas ethanol, even in very high concentrations, has little effect on the cytosolic Ca2+ concentration, several non-oxidative alcohol metabolites generate substantial and sustained global elevations of the cytosolic Ca2+ concentration and depolarize completely the inner mitochondrial membrane. The toxic effects of excessive alcohol intake are therefore not caused by ethanol directly, but rather by metabolites such as fatty acid ethyl esters. These act by emptying the intracellular Ca2+ stores, and because the mitochondrial function is also impaired the cell is unable to dispose of the Ca2+ released into the cytosol (Criddle et al., 2004).


This work was supported by an MRC Programme Grant. OHP is an MRC Research Professor.


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Corresponding author: Professor Ole H. Petersen FRS, MRC Secretory Control Research Group, The Physiological Laboratory, University of Liverpool, Crown Street, Liverpool L69 3BX, UK. Telephone: +44 151 794 5342,Fax: +44 151 794 5323, E-mail:

Received: April 4, 2004. Accepted: May 4, 2004.


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