The role of Ca2+ signalling in the pathology of exocrine pancreas

• Published in: Cell calcium (Edinburgh) 2023-06, Vol.112, p.102740-102740, Article 102740
• Main Authors: Gerasimenko, Julia V., Gerasimenko, Oleg V.
• Format: Article
• Language: English
• Subjects: Acute pancreatitis; Bcl-2 BH4 domain; Calcium signaling; Cell death; Galactose; Orai1/CRAC; Pancreatic macrophages; Pancreatic stellate cells
• ISSN: 0143-4160; 1532-1991
• DOI: 10.1016/j.ceca.2023.102740

•Ca2+ overload and ATP depletion are the main pathological processes in AP.•The CRAC channel is the most attractive therapeutic target to reduce excessive Ca2+ entry.•Modulation of IP3Rs and RyRs can efficiently inhibit pathological Ca2+ release.•Energy supplementation can effectively reduce ATP depletion in AP. Exocrine pancreas has been the field of many successful studies in pancreatic physiology and pathology. However, related disease - acute pancreatitis (AP) is still takes it toll with more than 100,000 related deaths worldwide per year. In spite of significant scientific progress and several human trials currently running for AP, there is still no specific treatment in the clinic. Studies of the mechanism of initiation of AP have identified two crucial conditions: sustained elevations of cytoplasmic calcium concentration (Ca2+ plateau) and significantly reduced intracellular energy (ATP depletion). These hallmarks are interdependent, i.e., Ca2+ plateau increase energy demand for its clearance while energy production is greatly affected by the pathology. Result of long standing Ca2+ plateau is destabilisation of the secretory granules and premature activation of the digestive enzymes leading to necrotic cell death. Main attempts so far to break the vicious circle of cell death have been concentrated on reduction of Ca2+ overload or reduction of ATP depletion. This review will summarise these approaches, including recent developments of potential therapies for AP. [Display omitted]