Adenylyl cyclase 6 mediates the action of cyclic AMP-dependent secretagogues in mouse pancreatic exocrine cells via protein kinase A pathway activation

Maria E. Sabbatini, Louis D'Alecy, Stephen I. Lentz, Tong Tang, John A. Williams

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14 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3693-3707
Number of pages15
JournalJournal of Physiology
Volume591
Issue number15
DOIs
StatePublished - Aug 1 2013

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Cyclic AMP-Dependent Protein Kinases
Cyclic AMP
Pancreatic Ducts
Vasoactive Intestinal Peptide
Protein Isoforms
Adenylyl Cyclases
Fluids and Secretions
Adenylate Kinase
Secretin
Amylases
Exocrine Pancreas
Calcineurin
Colforsin
Calmodulin
adenylyl cyclase 6
Pancreas
Calcium
Polymerase Chain Reaction
Membranes

ASJC Scopus subject areas

  • Physiology

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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. / Sabbatini, Maria E.; D'Alecy, Louis; Lentz, Stephen I.; Tang, Tong; Williams, John A.

In: Journal of Physiology, Vol. 591, No. 15, 01.08.2013, p. 3693-3707.

Research output: Contribution to journalArticle

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