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
Sanders, Kenton M; Salter, Anna K; Hennig, Grant W et al. (2014) Responses to enteric motor neurons in the gastric fundus of mice with reduced intramuscular interstitial cells of cajal. J Neurogastroenterol Motil 20:171-84
Zheng, Haifeng; Park, Kyung Sik; Koh, Sang Don et al. (2014) Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine. Am J Physiol Cell Physiol 306:C705-13
McCann, Conor J; Hwang, Sung-Jin; Hennig, Grant W et al. (2014) Bone Marrow Derived Kit-positive Cells Colonize the Gut but Fail to Restore Pacemaker Function in Intestines Lacking Interstitial Cells of Cajal. J Neurogastroenterol Motil 20:326-37
Durnin, Leonie; Hwang, Sung Jin; Kurahashi, Masaaki et al. (2014) Uridine adenosine tetraphosphate is a novel neurogenic P2Y1 receptor activator in the gut. Proc Natl Acad Sci U S A 111:15821-6
Okamoto, T; Barton, M J; Hennig, G W et al. (2014) Extensive projections of myenteric serotonergic neurons suggest they comprise the central processing unit in the colon. Neurogastroenterol Motil 26:556-70
Drumm, Bernard T; Koh, Sang Don; Andersson, Karl-Erik et al. (2014) Calcium signalling in Cajal-like interstitial cells of the lower urinary tract. Nat Rev Urol 11:555-64
Mutafova-Yambolieva, Violeta N; Durnin, Leonie (2014) The purinergic neurotransmitter revisited: a single substance or multiple players? Pharmacol Ther 144:162-91
Sanders, Kenton M; Ward, Sean M; Koh, Sang Don (2014) Interstitial cells: regulators of smooth muscle function. Physiol Rev 94:859-907
Kurahashi, Masaaki; Nakano, Yasuko; Peri, Lauren E et al. (2013) A novel population of subepithelial platelet-derived growth factor receptor *-positive cells in the mouse and human colon. Am J Physiol Gastrointest Liver Physiol 304:G823-34
Keef, K D; Saxton, S N; McDowall, R A et al. (2013) Functional role of vasoactive intestinal polypeptide in inhibitory motor innervation in the mouse internal anal sphincter. J Physiol 591:1489-506

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