Ca2+ oscillations in pancreatic acinar cells: spatiotemporal relationships and functional implications

doi:10.1016/0143-4160(93)90100-K

Cell Calcium

Volume 14, Issue 10, November 1993, Pages 746-757

https://doi.org/10.1016/0143-4160(93)90100-K Get rights and content

Abstract

The pancreatic acinar cells are of particular interest for the study of cytosolic Ca²⁺ signals, since they are morphologically polarized and generate agonist-specific Ca²⁺ oscillation patterns. Recent data obtained by combining digital video imaging of Fura-2 fluorescence with patch-clamp whole-cell current recording have provided new information on the spatiotemporal relationships of the cytosolic Ca²⁺ signals and the Ca²⁺-activated ionic currents. Low agonist concentrations evoke repetitive short-lasting local Ca²⁺ spikes in the secretory pole region that activate shortlasting current spikes. In the case of acetylcholine stimulation the spikes are confined to this region. When cholecystokinin is used the shortlasting local spikes precede longer Ca²⁺ transients that spread to the whole of the cell. Infusion of non-metabolizable inositol trisphosphate analogues can mimick these responses. The shortlasting local Ca²⁺ spikes are particularly sensitive to blockade by the inositol trisphosphate receptor antagonist heparin. These results show that the secretory pole region has a particularly high sensitivity to inositol trisphosphate probably due to clustering of high affinity receptors.

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Pancreatic acinar cells secrete fluid and digestive enzymes. Both types of secretion are activated by a rise in intracellular calcium but how the stimulus-secretion cascade actually regulates secretory output is not well understood. It has long been known that the calcium response of acinar cells to physiological stimulation is complex. Dependent on the type and concentration of agonist, it consists of either local or global calcium increases as well as spreading waves of calcium across the cell. In the past it has been speculated that these different calcium signals drive different secretory responses. Now, recent employment of two-photon microscopy has enabled the simultaneous recording of both enzyme secretion and calcium signals and is beginning to resolve this issue. The data shows that local calcium responses exclusively drive fluid secretion. Where-as, global calcium responses drive both fluid and enzyme secretion. This differential control of secretory output is likely central to controlling the physiological responses of pancreatic acinar cells.
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The highly polarized nature of epithelial cells in exocrine glands necessitates targeting, assembly into complexes and confinement of the molecules comprising the Ca²⁺ signaling apparatus, to cellular microdomains. Such high degree of polarized localization has been shown for all Ca²⁺ signaling molecules tested, including G protein coupled receptors and their associated proteins, Ca²⁺ pumps, Ca²⁺ influx channels at the plasma membrane and Ca²⁺ release channels in the endoplasmic reticulum. Although the physiological significance of polarized Ca²⁺ signaling is clear, little is known about the mechanism of targeting, assembly and retention of Ca²⁺ signaling complexes in cellular microdomains. The present review attempts to summarize the evidence in favor of polarized expression of Ca²⁺ signaling proteins at the apical pole of secretory cells with emphasis on the role of scaffolding proteins in the assembly and function of the Ca²⁺ signaling complexes. The consequence of polarized enrichment of Ca²⁺ signaling complexes at the apical pole is generation of an apical to basal pole gradient of cell responsiveness that, at low physiological agonist concentrations, limits Ca²⁺ spikes to the apical pole, and when a Ca²⁺ wave occurs, it always propagates from the apical to the basal pole. Our understanding of Ca²⁺ signaling in microdomains is likely to increase rapidly with the application of techniques to controllably and selectively disrupt components of the complexes and apply high resolution recording techniques, such as TIRF microscopy to this problem.
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We perform a bifurcation analysis of a model of Ca²⁺ wave propagation in the basal region of pancreatic acinar cells. The model we consider was first presented in Sneyd et al. [J. Sneyd, K. Tsaneva-Atanasova, J.I.E. Bruce, S.V. Straub, D.R. Giovannucci, D.I. Yule, A model of calcium waves in pancreatic and parotid acinar cells, Biophys. J. 85 (2003) 1392–1405], where a partial bifurcation analysis was given of the model in the absence of diffusion. We obtain more complete information about bifurcations of the diffusionless model via numerical studies, then analyse the spatially extended model by numerical investigation of the travelling wave equations and direct numerical solution of the model equations. We find solitary waves in the model equations arising from homoclinic bifurcations in the travelling wave equations. The solitary waves exist and appear to be stable for a significant interval of the primary bifurcation parameter (i.e., the concentration of inositol trisphosphate) but are eventually replaced by irregular spatio-temporal behaviour. The homoclinic bifurcations are related to a number of complicated mathematical structures in the travelling wave equations, including an anomalous homoclinic-Hopf bifurcation, heteroclinic bifurcations between an equilibrium and a periodic orbit, and homoclinic bifurcations of periodic orbits.
A model of calcium waves in pancreatic and parotid acinar cells
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Citation Excerpt :
Calcium waves at both high [IP3] and low [IP3] are initiated by Ca2+ release through the IPR, and extended by Ca2+ release through the RyR. That Ca2+ waves in pancreatic acinar cells begin in an apical zone, spreading thence across the cell, has been widely accepted for some years (Nathanson et al., 1992; Thorn et al., 1993a,b; Kasai et al., 1993; Lawrie et al., 1993; Thorn, 1996; Straub et al., 2000; Leite et al., 2002). Our results are essentially similar to these earlier conclusions.
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Ca2+ oscillations in pancreatic acinar cells: spatiotemporal relationships and functional implications

Abstract

FEBS Lett.

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Cell

Cell

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J. Biol. Chem.

Cell Calcium

Cell Calcium

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Bioorganic Med. Chem. Lett.

FEBS Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

FEBS Lett.

Stimulus secretion coupling: cytoplasmic calcium signals and the control of ion channels in exocrine acinar cells

J. Physiol.

Electrophysiology of pancreatic and salivary acinar cells

Annu. Rev. Physiol.

Inositol trisphosphate and calcium signalling

Nature

Two functionally distinct cholecystokinin receptors have different modes of action on Ca2+ mobilization and phospholipid hydrolysis in isolated rat pancreatic acini. Studies using a new cholecystokinin analogue, JMV-180

J. Biol. Chem.

Cholecystokinin-induced formation of inositol phosphates in pancreatic acini

Am. J. Physiol.

The role of cholecystokinin in inhibition of gastric emptying in the rat

Exp. Physiol.

Different patterns of receptor-activated cytoplasmic Ca2+ oscillations in single pancreatic acinar cells: dependence on receptor type, agonist concentration and intracellular buffering

EMBO J.

Discrete cytosolic Ca2+ spikes in the secretory pole of pancreatic acinar cells evoked by physiological cholecystokinin concentrations

Calcium oscillations in pancreatic acinar cells elicited by the CCK analogue JMV-180, are dependent on functional InsP3 receptors

Cytosolic Ca2+ gradients triggering unidirectional fluid secretion from exocrine pancreas

Nature

Ca²⁺ oscillations in pancreatic acinar cells: spatiotemporal relationships and functional implications

Two functionally distinct cholecystokinin receptors have different modes of action on Ca²⁺ mobilization and phospholipid hydrolysis in isolated rat pancreatic acini. Studies using a new cholecystokinin analogue, JMV-180

Different patterns of receptor-activated cytoplasmic Ca²⁺ oscillations in single pancreatic acinar cells: dependence on receptor type, agonist concentration and intracellular buffering

Discrete cytosolic Ca²⁺ spikes in the secretory pole of pancreatic acinar cells evoked by physiological cholecystokinin concentrations

Calcium oscillations in pancreatic acinar cells elicited by the CCK analogue JMV-180, are dependent on functional InsP₃ receptors

Cytosolic Ca²⁺ gradients triggering unidirectional fluid secretion from exocrine pancreas