1538-P: KCNQ2/3 Voltage Gated Potassium Channels Regulate the Activity of Intrapancreatic Neurons

Introduction & Objective: Input from the parasympathetic nervous system is necessary to adapt pancreatic islet and acinar function to the internal and behavioral status of an organism. pancreancreatic neurons, which form a vast interconnected ganglionated plexus, serve as mandatory targets of the parasympathetic vagus nerve. However, the exact mechanisms by which this local neuronal network conveys parasympathetic signals to the endocrine and exocrine pancreas are not well understood.

Methods: To interrogate the physiology of local pancreatic neurons in response to cholinergic input, we generated living pancreas slices from transgenic mice expressing the genetically encoded calcium indicator GCaMP3 in cholinergic neurons.

Results: We found that pancreatic neurons exhibit differential intracellular Ca2+ dynamics in response to nicotinic (nAChR) and/or muscarinic acetylcholine receptor (mAChR) agonists. While the nAChR agonist nicotine produces a single transient of intracellular Ca2+, the mAChR agonist Oxotremorine-M produces a long lasting Ca2+ response consisting of several oscillations. Furthermore, we were able to show that the intracellular Ca2+ responses elicited by Oxotremorine-M could be suppressed by compounds that activate KCNQ2/3 channels—voltage gated potassium channels that regulate membrane excitability. Concomitant application of KCNQ2/3 channel activators retigabine or ICA-069673 with Oxotremorine-M resulted in a roughly 60% reduction in response duration and number of Ca2+ transients.

Conclusion: These data suggest that pancreatic neurons may not represent canonical postganglionic neurons of the parasympathetic nervous system since they respond to mAChR stimulation and that KCNQ2/3 channel function may be required for the delivery of cholinergic input to pancreatic tissues. These data aid in providing a more complete understanding of the autonomic control of pancreas physiology and provide insight for potential therapeutic targets.