Calcium signalling in the acinar environment of the exocrine pancreas: physiology and pathophysiology

Abstract

Key points Ca2+ signalling in different cell types in exocrine pancreatic lobules was monitored simultaneously and signalling responses to various stimuli were directly compared.Ca2+ signals evoked by K+‐induced depolarization were recorded from pancreatic nerve cells. Nerve cell stimulation evoked Ca2+ signals in acinar but not in stellate cells.Stellate cells are not electrically excitable as they, like acinar cells, did not generate Ca2+ signals in response to membrane depolarization.The responsiveness of the stellate cells to bradykinin was markedly reduced in experimental alcohol‐related acute pancreatitis, but they became sensitive to stimulation with trypsin.Our results provide fresh evidence for an important role of stellate cells in acute pancreatitis. They seem to be a critical element in a vicious circle promoting necrotic acinar cell death. Initial trypsin release from a few dying acinar cells generates Ca2+ signals in the stellate cells, which then in turn damage more acinar cells causing further trypsin liberation. AbstractPhysiological Ca2+ signals in pancreatic acinar cells control fluid and enzyme secretion, whereas excessive Ca2+ signals induced by pathological agents induce destructive processes leading to acute pancreatitis. Ca2+ signals in the peri‐acinar stellate cells may also play a role in the development of acute pancreatitis. In this study, we explored Ca2+ signalling in the different cell types in the acinar environment of the pancreatic tissue. We have, for the first time, recorded depolarization‐evoked Ca2+ signals in pancreatic nerves and shown that whereas acinar cells receive a functional cholinergic innervation, there is no evidence for functional innervation of the stellate cells. The stellate, like the acinar, cells are not electrically excitable as they do not generate Ca2+ signals in response to membrane depolarization. The principal agent evoking Ca2+ signals in the stellate cells is bradykinin, but in experimental alcohol‐related acute pancreatitis, these cells become much less responsive to bradykinin and then acquire sensitivity to trypsin. Our new findings have implications for our understanding of the development of acute pancreatitis and we propose a scheme in which Ca2+ signals in stellate cells provide an amplification loop promoting acinar cell death. Initial release of the proteases kallikrein and trypsin from dying acinar cells can, via bradykinin generation and protease‐activated receptors, induce Ca2+ signals in stellate cells which can then, possibly via nitric oxide generation, damage more acinar cells and thereby cause additional release of proteases, generating a vicious circle.

The Orai Ca2+ channel inhibitor CM4620 targets both parenchymal and immune cells to reduce inflammation in experimental acute pancreatitis

“…In support of the concept that SOCE inhibition in PaSCs may attenuate its negative actions on acini within the pancreatic microenvironment, a recent study (Gryshchenko et al . ) reported a pathophysiological mechanism whereby dying acinar cells promote Ca 2+ signals in PaSCs, which then further damage acinar cells in a vicious cycle. In summary, it is clear that SOCE responses in multiple cell types, including inflammatory cells, PaSCs and acinar cells contribute both to individual and integrated pathobiological pathways during acute pancreatitis.…”

Gordon Research Conference on Ca2+ Signalling 2017 Editorial

“…PS cells are now less responsive to bradykinin but respond strongly to trypsin, and this is likely to contribute to a positive feedback cycle that promotes acute pancreatitis progression (Gryshchenko et al . ; Hegyi, ).…”

“…However, this changes dramatically when pancreatic lobules are either exposed to a mixture of ethanol and palmitoleic acid (to mimic acute pancreatitis in vitro) or are derived from mice in which acute pancreatitis has been induced in vivo. PS cells are now less responsive to bradykinin but respond strongly to trypsin, and this is likely to contribute to a positive feedback cycle that promotes acute pancreatitis progression (Gryshchenko et al 2018;Hegyi, 2018). An interesting twist on how an intracellular Ca 2+ rise can promote disease progression has been identified in cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells (Zhou et al 2018).…”

Necrotic amplification loop in acute pancreatitis: pancreatic stellate cells and nitric oxide are important players in the development of the disease

“…In this issue of The Journal of Physiology , Gryshchenko et al . () describe new mechanisms which add a very important piece to the puzzle of the AP pathomechanism. The authors very elegantly record Ca 2+ signalling in different cell types in the exocrine pancreatic lobules.…”

“…) and the necrotic amplification loop (Gryshchenko et al . ) must be blocked to develop a specific therapy for AP. Because of the multifactorial pathomechanism, several combinations of CFTR correctors/activators, bradykinin receptor antagonists, protease‐activated receptor antagonists, nitric oxide synthase inhibitors, store‐operated Ca 2+ entry blockers and mitochondrial permeability transition pore inhibitors should be tested.…”