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Adenylyl cyclase 6 mediates the action of cyclic AMP‐dependent secretagogues in mouse pancreatic exocrine cells via protein kinase A pathway activation
Author(s) -
Sabbatini Maria E.,
D’Alecy Louis,
Lentz Stephen I.,
Tang Tong,
Williams John A.
Publication year - 2013
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2012.249698
Subject(s) - adenylyl cyclase , protein kinase a , biology , gene isoform , intracellular , protein kinase c , medicine , secretin , endocrinology , pancreas , signal transduction , kinase , microbiology and biotechnology , biochemistry , gene
Key points• Cyclic AMP (cAMP), produced from ATP and the enzyme adenylyl cyclase (AC), plays an important role in the regulation of pancreatic exocrine cells. • We identified five AC isoforms in pancreatic exocrine cells. AC3, AC4, AC6 and AC9 are expressed in both pancreatic acini and duct fragments, whereas AC7 is expressed only in duct fragments. • In mice deficient in AC6, cAMP formation and protein kinase A activation were impaired. As a consequence, a reduction in amylase secretion and pancreatic fluid production was observed. • These results indicate that AC6 plays a regulatory role in pancreatic exocrine cells.Abstract Both secretin and vasoactive intestinal polypeptide (VIP) receptors are responsible for the activation of adenylyl cyclases (ACs), which increase intracellular cyclic AMP (cAMP) levels in the exocrine pancreas. There are nine membrane‐associated isoforms, each with its own pattern of expression and regulation. In this study we sought to establish which AC isoforms play a regulatory role in pancreatic exocrine cells. Using RT‐PCR, AC3, AC4, AC6, AC7 and AC9 were found to be expressed in the pancreas. AC3, AC4, AC6 and AC9 were expressed in both pancreatic acini and ducts, whereas AC7 was expressed only in pancreatic ducts. Based on known regulation by intracellular signals, selective inhibitors and stimulators were used to suggest which isoforms play an important role in the induction of cAMP formation. AC6 appeared to be an important isoform because protein kinase A (PKA), PKC and calcium all inhibited VIP‐induced cAMP formation, whereas calcineurin or calmodulin did not modify the response to VIP. Mice with genetically deleted AC6 were studied and showed reduced cAMP formation and PKA activation in both isolated pancreatic acini and duct fragments. The absence of AC6 reduced cAMP‐dependent secretagogue‐stimulated amylase secretion, and abolished fluid secretion in both in vivo and isolated duct fragments. In conclusion, several AC isoforms are expressed in pancreatic acini and ducts. AC6 mediates a significant part of pancreatic amylase and fluid secretion in response to secretin, VIP and forskolin through cAMP/PKA pathway activation.