Physiology of Acinar Cell Secretion

The acinar cell is the key element in the exocrine pancreas, producing and secreting the enzymes needed for the digestion of food. The secretory process is tightly regulated by the neurotransmitter acetylcholine, released from vagal nerve endings, and the hormone cholecystokinin. The initial signal transduction pathways employed by these two stimuli differ markedly but then converge, generating repetitive transient elevations in the calcium ion concentration in the apical part of the cytosol containing the zymogen granules. Each individual local calcium transient generates a short-lasting exocytotic burst of enzyme secretion by triggering fusion of zymogen granules with the apical plasma membrane. The local apical calcium signals also stimulate the production of a neutral chloride-rich fluid secretion by activating chloride channels specifically located in the apical membrane and potassium channels located specifically in the lateral membranes. The apical calcium signals are confined to this locality by the peri-granular mitochondria that take up calcium ions during each apical calcium spike. The rise in the intra-mitochondrial calcium ion concentration activates the Krebs cycle, generating adenosine triphosphate (ATP) needed to sustain the secretory processes. In contrast to the local calcium signals, generated by physiological levels of stimulation by acetylcholine or cholecystokinin, the excessive global calcium signals elicited by a combination of alcohol and fatty acids, or bile acids, do not generate ATP, but actually reduce mitochondrial ATP production. Such excessive calcium signals also release free trypsin into the cytosol, initiating a destructive process that is enhanced by necrotic amplification loops involving calcium-dependent interactions with neighboring stellate cells and macrophages invading the pancreas in the initial stages of acute pancreatitis.