Activation of pancreatic acinar cells by very low concentrations of cholecystokinin: mechanism and implications for physiology and pathology

ABSTRACT Cholecystokinin (CCK) is one of the three classical gut hormones. CCK is also, in contrast to the other two principal gut hormones (gastrin and secretin), an important neurotransmitter with widespread actions in the brain and in the periphery. Although not signposted by its name, one of the key physiological actions of CCK is to activate the secretion of an enzyme-rich neutral fluid produced by the pancreatic acinar cells. In general, hormones activate their target cells at concentrations that are much lower than those of neurotransmitters but, even in this context, the pancreatic acinar cells are extraordinarily sensitive to extremely low CCK concentrations (low pM). We explore the mechanism underlying this exceptional sensitivity as well as its consequences. The focus is on the intracellular transduction pathways that are activated when acinar cell CCK receptors are excited by the hormone. Uniquely, three different intracellular receptors – all linked to release of Ca 2+ from intracellular stores – are required for CCK to elicit secretion. The implications of this unusual arrangement for both pancreatic physiology and pathophysiology is discussed.