Regulation of protein phosphorylation in pancreatic acini by cyclic AMP-mediated secretagogues: interaction with carbamylcholine

Burnham, Daniel B.; Sung, Chin K.; Munowitz, P; Williams, John A.

doi:10.1016/0167-4889(88)90085-7

Cited by 17 publications

(13 citation statements)

References 19 publications

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“…By contrast, in mouse pancreatic acinar cells, PKA does not appear to participate in the process. Although PKA catalyzes the phosphorylation of regulatory proteins associated with pancreatic exocytotic process (43,44), our current study showed that the Epac1/Rap1 pathway, but not the PKA pathway, has a relevant role in cAMP-stimulated amylase release (Fig. 8, C and D).…”

Section: Discussionmentioning

confidence: 91%

Rap1 Activation Plays a Regulatory Role in Pancreatic Amylase Secretion

Sabbatini

Chen

Ernst

et al. 2008

Journal of Biological Chemistry

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Rap1 is a member of the Ras superfamily of small GTP-binding proteins and is localized on pancreatic zymogen granules. The current study was designed to determine whether GTPRap1 is involved in the regulation of amylase secretion. Rap1A/B and the two Rap1 guanine nucleotide exchange factors, Epac1 and CalDAG-GEF III, were identified in mouse pancreatic acini. A fraction of both Rap1 and Epac1 colocalized with amylase in zymogen granules, but only Rap1 was integral to the zymogen granule membranes. Stimulation with cholecystokinin (CCK), carbachol, and vasoactive intestinal peptide all induced Rap1 activation, as did calcium ionophore A23187, phorbol ester, forskolin, 8-bromo-cyclic AMP, and the Epac-specific cAMP analog 8-pCPT-2-O-Me-cAMP. The phospholipase C inhibitor U-73122 abolished carbachol-but not forskolin-induced Rap1 activation. Co-stimulation with carbachol and 8-pCPT-2-O-Me-cAMP led to an additive effect on Rap1 activation, whereas a synergistic effect was seen on amylase release. Although the protein kinase A inhibitor H-89 abolished forskolin-stimulated CREB phosphorylation, it did not modify forskolin-induced GTP-Rap1 levels, excluding PKA participation. Overexpression of Rap1 GTPase-activating protein, which blocked Rap1 activation, reduced the effect of 8-bromo-cyclic AMP, 8-pCPT-2-O-Me-cAMP, and vasoactive intestinal peptide on amylase release by 60% and reduced CCK-as well as carbachol-stimulated pancreatic amylase release by 40%. These findings indicate that GTP-Rap1 is required for pancreatic amylase release. Rap1 activation not only mediates the cAMPevoked response via Epac1 but is also involved in CCK-and carbachol-induced amylase release, with their action most likely mediated by CalDAG-GEF III.Rap1 is a member of the Ras superfamily of small GTP-binding proteins and is known to be involved in cell adhesion, proliferation, and differentiation (1). Two isoforms of Rap1 exist, Rap1A and Rap1B, which are 95% identical at the amino acid sequence and appear to mediate similar actions (1). Like other members of this superfamily of proteins, Rap1 cycles between an inactive GDP-bound and an active GTP-bound form. A variety of intracellular signals regulate the cycle through unique guanine-nucleotide exchange factors (GEFs), 2 which promote dissociation of GDP from Rap1 followed by binding of GTP, and GTPase-activating proteins (GAPs), which induce hydrolysis of GTP on Rap1 (1). Increases in intracellular levels of Ca 2ϩ and diacylglycerol (DAG) activate Ca 2ϩ -and DAG-binding GEFs (CalDAG-GEF I and CalDAG-GEF III) (2), whereas increases in intracellular levels of cAMP activate the exchange proteins activated by cAMP (Epac1 and Epac2) (3, 4). Protein kinase A (PKA), another mediator of cAMP action, can phosphorylate Rap1, which is necessary for Rap1 activation in certain cell types, including neutrophils, fibroblasts, thyroid and enteroendocrine cells (5-8).Evidence indicates that different endogenous Rap1GEFs exert physiological functions in various cells. For example, in neuronal PC12D cells, Ca...

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Section: Discussionmentioning

confidence: 91%

Rap1 Activation Plays a Regulatory Role in Pancreatic Amylase Secretion

Sabbatini

Chen

Ernst

et al. 2008

Journal of Biological Chemistry

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“…In contrast, the increase in enzyme secretion caused by the combination of two secretagogues with different intracellular mechanisms has been reported to be greater than the additive increase of the two individual secretagogues (Deschodt-Lanckman et al 1975; Gardner and Burnham et al 1984Burnham et al , 1987. In the present study, the enzyme secretion observed with the combination of PACAP 38 and an agonist working via cAMP (i.e., VIP and dibutyryl cAMP) was elevated, but was less than the calculated additive effect of enzyme release by the two secretagogues alone.…”

Section: Discussionmentioning

confidence: 99%

The Stimulatory Effect of PACAP 38 on Amylase Release in Dispersed Rat Pancreatic Acini.

Kashimura

Shimosegawa

Kikuchi

et al. 1991

Tohoku J. Exp. Med.

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Pituitary adenylate cyclase activating polypeptide 38 (PACAP 38), a novel peptide of the vasoactive intestinal polypeptide (VIP) family, was shown to stimulate enzyme secretion in the dispersed rat pancreatic acini. The dose-response of pancreatic enzyme secretion to PACAP 38 was nearly identical with that to VIP. In the presence of a submaximal dose of PACAP 38 (1 nM), amylase release stimulated by an agonist working via the elevation of intracellular cyclic AMP (VIP, dibutyryl CAMP) was additionally responded, but the amylase release stimulated by an agonist via the elevation of cytosolic free calcium (carbachol, cholecystokinin) was potentiated synergistically. The present data suggest that PACAP 38 is a new candidate for the cAMP-mediated stimulant of pancreatic exocrine secretion. PACAP 38; amylase release ; dispersed pancreatic acini ; ratPituitary adenylate cyclase activating polypeptide (PACAP) is a 38 amino acid-residue peptide of the vosoactive intestinal polypeptide (VIP) family recently isolated from the ovine hypothalamus.Its N-terminal 1-28 amino acid sequence possesses a 68% homology with that of porcine VIP. It has been reported that PACAP 38 stimulates the adenylate cyclase activity of rat pituitary cells and increases intracellular cAMP at least 1,000 times more than does VIP (Miyata et al. 1989). PACAP-like immunoreactivity (LI) has been immunohistochemically localized in nerve fibers and terminals distributed to the median eminence and pituitary stalk, suggesting a neurotransmitter, neuromodulator , or neurohormonal role for this peptide (Koves et al. 1990).Pancreatic enzyme secretion is under the control of hormones and nerves. Peptides of the VIP family such as secretin, VIP (Gardner and Jensen 1981) , peptide histidine isoleucine (PHI) and helodermin (Raufman

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“…For example, in isolated rat pancreatic acini both VIP and secretin potentiate amylase secretion stimulated by CCK or the cholinergic agonist carbachol [56,57]. A later study demonstrated that PKA is responsible for the modulation of Ca 2+ - and PKC-evoked amylase secretion in permeabilized rat pancreatic secretion [4].…”

Section: Role Of Ac In the Regulation Of Digestive Systemmentioning

confidence: 99%

Adenylyl cyclases in the digestive system

Sabbatini

Gorelick

Glaser

2014

Cellular Signalling

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Adenylyl cyclases (ACs) are a group of widely distributed enzymes whose functions are very diverse. There are nine known transmembrane AC isoforms activated by Gαs. Each has its own pattern of expression in the digestive system and differential regulation of function by Ca2+ and other intracellular signals. In addition to the transmembrane isoforms, one AC is soluble and exhibits distinct regulation. In this review, the basic structure, regulation and physiological roles of ACs in the digestive system are discussed.

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Regulation of protein phosphorylation in pancreatic acini by cyclic AMP-mediated secretagogues: interaction with carbamylcholine

Cited by 17 publications

References 19 publications

Rap1 Activation Plays a Regulatory Role in Pancreatic Amylase Secretion

Rap1 Activation Plays a Regulatory Role in Pancreatic Amylase Secretion

The Stimulatory Effect of PACAP 38 on Amylase Release in Dispersed Rat Pancreatic Acini.

Adenylyl cyclases in the digestive system

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