Justyna Magdalena Kowal:
Extracellular ATP in the exocrine pancreas – ATP release, signalling and metabolism

Date: 27-02-2015    Supervisor: Ivana Novak

ATP plays an important role as an autocrine/paracrine signalling molecule, being released from a number of tissues, in response to physiological and pathophysiological stimuli. Released ATP induces Ca2+ - and/or cAMP - dependent cellular responses via activation of ubiquitously expressed P2X and P2Y receptors. Previously, our group has shown that cholinergic stimulation of acini caused ATP release into ducts and ATP is an important regulator of ductal functions by being involved in ion and fluid secretion. Pancreatic duct cells are exposed to a number of stimuli, well known to induce ATP release. So far, the contribution of duct cells in purinergic signalling has never been studied.

This work presents that both acinar and duct cells are sources of extracellular ATP in the exocrine pancreas. Here we show that duct cells release ATP in response to several physiological and pathophysiological stimuli via vesicular and non-vesicular pathways. Furthermore, duct cells express ATP-hydrolysing and generating enzymes, which can possibly regulate the extracellular distribution of nucleotides. Interestingly, bile acids induced Ca2+ transients in duct cells which are in part due to purinergic signalling. Inhibition of P2X and P2Y receptors significantly reduced the cellular Ca2+ response after exposing the duct cells to a bile acid. Furthermore, we observed that the bile acid receptor TGR5 is expressed in duct cells and after its activation the receptor could have a protective effect on the cells, particularly during Ca2+ stress conditions. In conclusion, these studies demonstrate a complex regulation of purinergic signalling in exocrine pancreas. A crucial role for duct cells in mediating extracellular nucleotides homeostasis, involving ATP release, subsequent hydrolysis and conversion via extracellular enzymes is suggested. Bile acids were shown to be a novel ATP release stimuli, and some effects of bile acid induced signalling may in part be mediated via purinergic signalling.