This 5-year project of research on the enteric nervous system is designed to improve understanding of the cellular and molecular neurophysiology of secretomotor neurons in the intestinal submucosal plexus and inhibitory and excitatory motor neurons in the myenteric plexus that innervate the intestinal musculature. Cellular neurophysiology underlies functions of secretomotor neurons that are basic to control of fluidity of the intestinal contents in states of health and to diarrhea and constipation in disordered states. Cellular neurophysiology of musculomotor neurons is basic to control of muscular contraction in normal motility and disordered motility in disease states.
Aims of the project are based on pilot/feasibility results, which suggest that slow excitatory neurotransmission in enteric motor neurons is specialized and different from this form of synaptic transmission in other kinds of enteric neurons. The pilot/feasibility data for secretomotor and musculomotor neurons suggest that this class of neurons express in common the properties of uniaxonal morphology, S-type electrophysiological behavior, increased ionic conductance during slow excitatory neurotransmission, and a metabotropic signal transduction cascade that involves calmodulin kinases and protein kinase C, but not cAMP and protein kinase A. The project has five specific aims.
Aim 1 is organized to test the hypothesis that opening of non-selective cationic and perhaps chloride conductance channels accounts for the membrane depolarization seen during the slow EPSP in neurons identified morphologically and immunohistochemically as motor neurons in the myenteric and submucosal plexuses.
Aim 2 tests the hypothesis that activation of phospholipase C, IP3 release and mobilization of intraneuronal calcium are steps in the signal transduction cascade for the newly recognized slow EPSP in enteric motor neurons.
Aim 3 tests the hypothesis that calcium binding to calmodulin is a key step in the signaling mechanisms that underlie the specialized slow EPSP.
Aim 4 tests the expectation that calmodulin kinases II & IV and activation of protein kinase C are steps in the calcium signaling cascade for the EPSP.
Aim 5 tests suggestions that activation of protein kinase C by calmodulin kinases leads to phorphorylation and opening of the ionic channels that underlie depolarization of the membrane potential and enhanced excitability that occurs during slow synaptic excitation in enteric motor neurons. Dephosphorylation of the channels by the phosphatase, calcineurin, terminates slow EPSP. ? ? ?
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