Gastrointestinal (Gl) motility patterns depend, in part, on coordination of contractile activity by enteric motor neurons. Enteric excitatory and inhibitory motor neurons contribute to development of appropriate motor patterns in Gl organs. In the colon a prominent motor pattern, known as colonic migrating motor complexes (CMMC) provides propulsive forces for movement of fecal material in the anal direction. At present CMMC are thought to be based on the peristaltic reflex in which local stimuli generate ascending contractions and descending inhibition. This concept has become canonical in neurogastroenterology. In fact there is a 3rd phase of the peristaltic reflex that is poorly understood and infrequently even mentioned in scholariy reviews of peristalsis. Enteric motor neurons activate excitatory and inhibitory neurons and elicit region-dependent contraction and relaxation responses. In most regions of the gut, including the colon, the response to nerve stimulation is followed by a post-stimulus excitatory response (PSR also known as rebound excitation). We have discovered that PSR is actually an extremely important component, if not the main propulsive force, in propagating contractions (i.e. CMMC). CMMC are reduced by only an extent by muscarinic antagonists and not dependent upon excitatory peptides. CMMC are totally eliminated by inhibition of nitric oxide synthase in proximal colon or P2Y1 receptors in distal colon. Thus, CMMC are not dependent upon migrating responses to excitatory nerves but on migrating inhibitory responses coupled to PSR. There are striking similarities in PSR between species, and such a high degree of conservation tends to indicate the importance of PSR in colonic motility. Modifying canons, like the peristaltic reflex, requires careful investigation and determination of the mechanisms driving PSR. Our experiments will reveal the cell-specific steps and signaling pathways responsible for PSR and these findings will provide remarkable new ideas about managing colonic propulsive disorders. We will use reporter strains of transgenic mice for cell studies of PSR, and comparative studies on colonic muscles and whole colonic segments from mice, non-human primates, and human patients to develop a unified and mechanistic concept of PSR and its importance in propulsive movements.

Public Health Relevance

Slow transit constipation is a prevalent health care problem that has been assoicated with loss of interstitial cells of Cajal. In this project we will explore the role of ICC in generating propulsive contraction in the colon and show the consequences of a defect in these cells for nrormal colonic transit.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK041315-26
Application #
8742139
Study Section
Special Emphasis Panel (ZDK1-GRB-6 (J3))
Project Start
Project End
Budget Start
2014-08-20
Budget End
2015-07-31
Support Year
26
Fiscal Year
2014
Total Cost
$190,350
Indirect Cost
$57,702
Name
University of Nevada Reno
Department
Type
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Durnin, Leonie; Lees, Andrea; Manzoor, Sheerien et al. (2017) Loss of nitric oxide-mediated inhibition of purine neurotransmitter release in the colon in the absence of interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol 313:G419-G433
Drumm, Bernard T; Hennig, Grant W; Battersby, Matthew J et al. (2017) Clustering of Ca2+ transients in interstitial cells of Cajal defines slow wave duration. J Gen Physiol 149:703-725
Cobine, C A; Hannah, E E; Zhu, M H et al. (2017) ANO1 in intramuscular interstitial cells of Cajal plays a key role in the generation of slow waves and tone in the internal anal sphincter. J Physiol 595:2021-2041
Lee, Moon Young; Park, Chanjae; Ha, Se Eun et al. (2017) Serum response factor regulates smooth muscle contractility via myotonic dystrophy protein kinases and L-type calcium channels. PLoS One 12:e0171262
Beckett, Elizabeth A H; Sanders, Kenton M; Ward, Sean M (2017) Inhibitory responses mediated by vagal nerve stimulation are diminished in stomachs of mice with reduced intramuscular interstitial cells of Cajal. Sci Rep 7:44759
Sung, Tae Sik; O'Driscoll, Kate; Zheng, Haifeng et al. (2016) Influence of intracellular Ca2+ and alternative splicing on the pharmacological profile of ANO1 channels. Am J Physiol Cell Physiol 311:C437-51
Sanders, Kenton M; Ward, Sean M; Friebe, Andreas (2016) Rebuttal from Kenton M. Sanders, Sean M. Ward and Andreas Friebe. J Physiol 594:1515
Durnin, L; Moreland, N; Lees, A et al. (2016) A commonly used ecto-ATPase inhibitor, ARL-67156, blocks degradation of ADP more than the degradation of ATP in murine colon. Neurogastroenterol Motil 28:1370-81
Sanders, Kenton M; Ward, Sean M; Friebe, Andreas (2016) CrossTalk proposal: Interstitial cells are involved and physiologically important in neuromuscular transmission in the gut. J Physiol 594:1507-9
Durnin, Leonie; Hayoz, Sebastien; Corrigan, Robert D et al. (2016) Urothelial purine release during filling of murine and primate bladders. Am J Physiol Renal Physiol 311:F708-F716

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