Roles of mechanosensory ion channels in myenteric intrinsic primary afferent neurons

肠神经系统是自主神经系统的一个独立分支，自主神经系统包含对肠道压迫作出反应的感觉神经元。然而，完全包含在肠壁中的完整神经系统的概念仍在建立中，部分依赖于证明肠道中存在内在感觉神经元并研究它们的功能特性。与收缩肠道及其推进性反射有关的特别重要的是内在机械敏感感觉神经元的兴奋性。我们知道蠕动传播的运动复合体依赖于内在的肌内感觉神经元，因为实验上沉默这些神经元会导致推进抑制、停滞和死亡。尽管许多类型的myenteric神经元（和其他类型的细胞）已被证明对拉伸或诽谤有反应，但我们已经确定了一种化学敏感的myenteric intrinsic primary传入神经元（IPAN），其放电速率由s压缩调节。此外，我们提供的证据表明，在IPANs中存在拉伸敏感通道（体细胞BK和轴突阳离子通道），而在其他类型的肌肠神经元中尚未发现类似的通道。因此，我们为IPANs机械感觉作用的分子基础提供了初步的实验数据。我们的实验旨在系统地研究ipan中拉伸敏感通道的特性，以帮助理解这些感觉神经元将机械信号与其兴奋性的其他决定因素相结合。

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.