Effects of Calmodulin Inhibitors on Amylase Secretion from Rat Pancreatic Acini

Ishiguro, Hiroshi; Hayakawa, Tetsuo; Kondo, Takaharu; Shibata, Tokimune; Kitagawa, Motoji; Sakai, Yuzo; Sano, Hiroshi; Nakae, Yasuyuki; Tanikawa, Makoto; Hidaka, Hiroyoshi

doi:10.1159/000201001

Cited by 12 publications

(5 citation statements)

References 13 publications

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“…The data confirm previous findings by the same group that CaMKIV, but not CaMKII, is involved in activation of calcium-dependent enzyme secretion (316). This particular result actually contradicts a study by a different group that implicated CaMKII in regulated enzyme secretion in pancreas (123).…”

Section: Effects On Exocrine Secretionsupporting

confidence: 79%

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Polarized Calcium and Calmodulin Signaling in Secretory Epithelia

Ashby

Tepikin

2002

Physiological Reviews

106

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This review examines polarized calcium and calmodulin signaling in exocrine epithelial cells. The calcium ion is a simple, evolutionarily ancient, and universal second messenger. In exocrine epithelial cells, it regulates essential functions such as exocytosis, fluid secretion, and gene expression. Exocrine cells are structurally polarized, with the apical region usually dedicated to secretion. Recent advances in technology, in particular the development of videoimaging and confocal microscopy, have led to the discovery of polarized, subcellular calcium signals in these cell types. The properties of a rich variety of local and global calcium signals have now been described in secretory epithelial cells. Secretagogues stimulate apical-to-basal waves of calcium in many exocrine cell types, but there are some interesting exceptions to this rule. The shapes of intracellular calcium signals are determined by the distribution of calcium-releasing channels and mechanisms that limit calcium elevation. Polarized distribution of calcium-handling mechanisms also leads to transcellular calcium transport in exocrine epithelial cells. This transport can deliver considerable amounts of calcium into secreted fluids. Multicellular polarized calcium signals can coordinate the activity of many individual cells in epithelial secretory tissue. Certain particularly sensitive cells serve as pacemakers for initiation of intercellular calcium waves. Many calcium signaling pathways involve activation of calmodulin. This ubiquitous protein regulates secretion in exocrine cells and also activates interesting feedback interactions with calcium channels and transporters. Very recently it became possible to directly study polarized calcium-calmodulin reactions and to visualize the process of hormone-induced redistribution of calmodulin in live cells. The structural and functional polarity of secretory epithelia alongside the polarity of its calcium and calmodulin signaling present an interesting lesson in tissue organization.

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Section: Effects On Exocrine Secretionsupporting

confidence: 79%

“…Pancreatic acinar cells also express CaMKII and CaMKIV (316). The CaM inhibitor W-7 and the CaMKII inhibitor KN-62 reduced stimulated amylase secretion (123). Cyclosporin A, an inhibitor of CaM-dependent protein phosphatase PP2B (or calcineurin), also inhibits amylase release triggered by CCK and by CCh (104).…”

Section: Effects On Exocrine Secretionmentioning

confidence: 99%

Polarized Calcium and Calmodulin Signaling in Secretory Epithelia

Ashby

Tepikin

2002

Physiological Reviews

106

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“…Interestingly, exocytosis-incompetent strains become responsive when transfected with the CaM wildtype gene [54]. In sea urchin egg [55], mast cells [56] and in pancreatic acinar cells [57] CaM was considered to confer calcium sensitivity. (7) Recently the involvement of a CaN-mediated dephosphorylation step in exocytosis has been ascertained also with several other cell types, i.e.…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatase and kinase activities possibly involved in exocytosis regulation in Paramecium tetraurelia

Kissmehl

Treptau

Hofer

et al. 1996

Biochemical Journal

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In Paramecium tetraurelia cells synchronous exocytosis induced by aminoethyldextran (AED) is accompanied by an equally rapid dephosphorylation of a 63 kDa phosphoprotein (PP63) within 80 ms. In vivo, rephosphorylation occurs within a few seconds after AED triggering. In homogenates (P)P63 can be solubilized in all three phosphorylation states (phosphorylated, dephosphorylated and rephosphorylated) and thus tested in vitro. By using chelators of different divalent cations, de- and rephosphorylation of PP63 and P63 respectively can be achieved by an endogenous protein phosphatase/kinase system. Dephosphorylation occurs in the presence of EDTA, whereas in the presence of EGTA this was concealed by phosphorylation by endogenous kinase(s), thus indicating that phosphorylation of P63 is calcium-independent. Results obtained with protein phosphatase inhibitors (okadaic acid, calyculin A) allowed us to exclude a protein serine/threonine phosphatase of type I (with selective sensitivity in Paramecium). Protein phosphatase 2C is also less likely to be a candidate because of its requirement for high Mg2+ concentrations. According to previous evidence a protein serine/threonine phosphatase of type 2B (calcineurin; CaN) is possibly involved. We have now found that bovine brain CaN dephosphorylates PP63 in vitro. Taking into account the specific requirements of this phosphatase in vitro, with p-nitrophenyl phosphate as a substrate, we have isolated a cytosolic phosphatase of similar characteristics by combined preparative gel electrophoresis and affinity-column chromatography. In Paramecium this phosphatase also dephosphorylates PP63 in vitro (after 32P labelling in vivo). Using various combinations of ion exchange, affinity and hydrophobic interaction chromatography we have also isolated three different protein kinases from the soluble fraction, i.e. a cAMP-dependent protein kinase (PKA), a cGMP-dependent protein kinase (PKG) and a casein kinase. Among the kinases tested, PKA cannot phosphorylate P63, whereas either PKG or the casein kinase phosphorylate P63 in vitro. On the basis of these findings we propose that a protein phosphatase/kinase system is involved in the regulation of exocytosis in P. tetraurelia cells.

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“…cAMP also caused Ca2+-independent secretion of amylase and luteinizing-hormone in permeabilized parotid acini (32) and pituitary cells (33), respectively. On the other hand, cAMP potentiated Ca 2+-dependent secretion of amylase in permeabilized pancreatic acinar cells (34,35), and the amylase secretion by both Ca 2+ and cAMP was inhibited by W-7, a calmodulin inhibitor, and KN-62, a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II (36), suggesting an interaction between Ca 2+ and cAMP via the Ca 2+/calmodulin complex in the secretory process. cAMP also enhanced Ca2+-dependent secretion in permeabilized RINm5F cells (37).…”

Section: Discussionmentioning

confidence: 98%

Effect of cAMP-Dependent Protein Kinase on Catecholamine Secretion from Bovine Adrenal Chromaffin Cells

Tachikawa

Furumachi

Yanagihara

et al. 1995

Japanese Journal of Pharmacology

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We examined the role of cAMP-dependent protein kinase in Ca"-elicited catecholamine secretion from bovine adrenal chromaffin cells. When the digitonin-treated cells were incubated with the catalytic subunit of cAMP-dependent protein kinase, the secretion of catecholamines from the cells occurred in the absence of Ca 2+. The effect of the catalytic subunit was dependent on its activity (50-100 units/ml) and the presence of ATP-Mg2+ in the incubation medium. However, incubation of the cells with the regulatory subunit of cAMP-dependent protein kinase did not affect the secretion. Ca 2+ (43 nM -10 [M) also increased the secretion, which was ATP-Mg2+-dependent.The catalytic subunit (25-200 units/ml) enhanced the Ca2+-evoked secretion at the suboptimal but not optimal Ca 21 concentration, which induced maximal secretion. A potent synthetic peptide inhibitor of cAMP-dependent protein kinase abolished the catalytic subunit-induced secretion, but not the Ca2+-evoked secretion. On the other hand, K252a, a potent inhibitor of protein kinases, inhibited both the catalytic subunit-induced and the Ca2+-evoked secretion, but not KT5823, a much less potent inhibitor of protein kinases. These results strongly suggest that the catalytic subunit of cAMP-dependent protein kinase produces the secretion of catecholamines via protein phosphorylation. The results further suggest that the cAMP-dependent protein kinase does not participate in an intrinsic process of Ca2+-elicited secretion but it may act as a modulator.

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Effects of Calmodulin Inhibitors on Amylase Secretion from Rat Pancreatic Acini

Cited by 12 publications

References 13 publications

Polarized Calcium and Calmodulin Signaling in Secretory Epithelia

Polarized Calcium and Calmodulin Signaling in Secretory Epithelia

Protein phosphatase and kinase activities possibly involved in exocytosis regulation in Paramecium tetraurelia

Effect of cAMP-Dependent Protein Kinase on Catecholamine Secretion from Bovine Adrenal Chromaffin Cells

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