Roles of mechanosensory ion channels in myenteric intrinsic primary afferent neurons

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The enteric nervous system is an independent division of the autonomic nervous system which contains its own in sensory neurons that respond to gut compression. However, the concept of a complete nervous system contained entirely in the wall of the intestine is still being established and relies in part on showing that there are intrinsic sensory neurons in the gut and studying their functional properties. Of particular importance in relation to the contracting gut and its propulsive reflexes is the excitability intrinsic mechanosensitive sensory neurons. We know that peristaltic propagated motor complexes depend on intrinsic myenteric sensory neurons, because experimentally silencing these neurons causes inhibition of propulsion, stasis and death. Although many types of myenteric neurons (and other types of cells) have been shown to respond to stretch or defamation, we have identified a type of chemosensitive myenteric intrinsic primary afferent neuron (IPAN) whose firing rate is modulated by s compression. Moreover, we provide evidence for stretch sensitive channels (somatic BK and axonic cationic channels) in IPANs, and no equivalent has so far been found in other types of myenteric neurons. We have thus provided beginning experimental data for molecular basis for a mechanosensory role for IPANs. Our experiments are designed to systematically study the properties of stretch sensitive channels in IPANs to help understand these sensory neurons integrate mechanical signals with other determinants of their excitability.*Stretch sensitive ion channels provide the link between gut movement and how IPANs sense and respond to distension to initiate peristalsis. We have already uniquely recorded currents from mechanosensitive BK channels in myenteric IPANs and shown that BK opening inhibits neuron firing. We now plan to quantitatively measure BK channel currents to make a best fit model of its opening and closing properties. This will help us in understanding how determinants of channel opening interact to influence the overall mechanosensitive current. We establish if BK channel opening is affected by intracellular calcium, gut hormones, with each fact integrated into the model. IPANs, unlike spinal or vagal sensory neurons. Receive synaptic input adding another dimension to their functional repertoire. The effect effects of synaptic input on BK channels will also be determined experimentally. *Excitatory stretch sensitive channels on the sensory neuron's axons have been indirectly inferred from our experiments. These are extremely important in initiating sensory neuron firing and thus peristalsis yet they have not been identified as to their identity or response characteristics. We will perform stimulus-response experiments and ion substitution experiments to identify for the first time which neuronal channels initiate peristalsis. This work will provide the first molecular physiological study of the mechanisms that control of gut motility at the neurone cellular level and will expand the understanding of how the intestine responds to stimuli, independent of the central or other autonomic nervous systems. Because little is presently known about gut IPAN mechanotransduction compared to other sensory systems, our work will help increase knowledge in gut sensory physiology at a level of detail not presently available. This work will benefit Canadian gut sensory neuroscience research in which my laboratory is at the forefront of myenteric neuron sensory physiology.