期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 294, 期 6, 页码 G1328-G1334出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00440.2007
关键词
calcium signaling; pancreatitis; zymogen activation; exocrine pancreas
资金
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [K12HD001401] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K08DK068116, R03DK078707] Funding Source: NIH RePORTER
- NICHD NIH HHS [K12 HD001401, K12 HD-001401] Funding Source: Medline
- NIDDK NIH HHS [R03 DK078707, K08 DK068116-04, K08 DK068116-01, K08 DK-68116, K08 DK068116, R03 DK078707-01A1, K08 DK068116-03, K08 DK068116-02] Funding Source: Medline
Cytosolic Ca2+ (Ca-i(2+)) flux within the pancreatic acinar cell is important both physiologically and pathologically. We examined the role of cAMP in shaping the apical-to-basal Ca2+ wave generated by the Ca2+-activating agonist carbachol. We hypothesized that cAMP modulates intra-acinar Ca2+ channel opening by affecting either cAMP-dependent protein kinase (PKA) or exchange protein directly activated by cAMP (Epac). Isolated pancreatic acinar cells from rats were stimulated with carbachol (1 mu M) with or without vasoactive intestinal polypeptide (VIP) or 8-bromo-cAMP (8-Br-cAMP), and then Ca-i(2+) was monitored by confocal laser-scanning microscopy. The apical-to-basal carbachol (1 mu M)-stimulated Ca2+ wave was 8.63 +/- 0.68 mu m/s; it increased to 19.66 +/- 2.22 mu m/s (*P < 0.0005) with VIP (100 nM), and similar increases were observed with 8-Br-cAMP (100 mu M). The Ca2+ rise time after carbachol stimulation was reduced in both regions but to a greater degree in the basal. Lag time and maximal Ca2+ elevation were not significantly affected by cAMP. The effect of cAMP on Ca2+ waves also did not appear to depend on extracellular Ca2+. However, the ryanodine receptor (RyR) inhibitor dantrolene (100 mu M) reduced the cAMP-enhancement of wave speed. It was also reduced by the PKA inhibitor PKI (1 mu M). 8-(4-chlorophenylthio)2'-O-Me-cAMP, a specific agonist of Epac, caused a similar increase as 8-Br-cAMP or VIP. These data suggest that cAMP accelerates the speed of the Ca2+ wave in pancreatic acinar cells. A likely target of this modulation is the RyR, and these effects are mediated independently by PKA and Epac pathways.
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