Mechanisms of parasympathetic cholinergic control of pancreatic cell function

It is generally recognized that the parasympathetic nervous system uses the vagus nerve to control insulin and digestive enzyme secretion from the pancreas. However, the neurotransmission mechanisms between the vagus nerve and the final targets in the pancreas have not been fully elucidated. Here we show that intrapancreatic neurons are the exclusive pancreatic targets of vagal efferent fibers, respond to vagal stimulation, react to cholinergic input with nicotinic and muscarinic receptors, and activate target cells in the pancreas. Using chemogenetic stimulation of intrapancreatic neurons in living pancreatic slices, we demonstrate that activation of muscarinic receptor signaling and concomitant closure of Kv7 potassium channels in neurons is required to efficiently stimulate acinar and islet cells. This mechanistic insight into how intrapancreatic neurons transmit vagal input to regulate pancreas function contradicts canonical models of neurotransmission at parasympathetic postganglionic neurons and is critical to develop vagus nerve electroceutical devices to treat diabetes and pancreatitis.