Normal motor activity in the gastrointestinal (GI) tract relies upon coordinated contractions of the smooth muscle cells (SMCs) that line its walls. The ultimate contractile behavior of GI muscles depends upon the state of SMC excitability when regulatory inputs (e.g. nerve reflexes, hormones, etc) are applied. This project has developed the concept of the SIP syncytium, an electrically coupled tissue consisting of SMCs, interstitial cells of Cajal and PDGFRa+ cells, that establishes the basal excitability of smooth muscles, organizes contractile behavior into phasic contractions, and transduces signals from a variety of motor neurons. GI motility in fact results from the integrated output of the SIP syncytium. During the past funding period we discovered that PDGFRa+ cells are a novel class of regulatory cells and essential component of the SIP syncytium. These cells express receptors and ion channels consistent with mediation of purinergic inhibitory regulation in the GI tract. Through isolation and purification of PDGFRa+ cells by FACS we performed deep sequencing to better understand the phenotypes of these cells. The expression data suggest that many additional pathways, such as adrenergic and inhibitory neuropeptides, contribute to the regulatory functions of PDGFRa+ cells. The focus of the upcoming funding period is to test the hypothesis that sympathetic nerve and enteric inhibitory neuropeptide signals are also transduced by PDGFRa+ cells, making these cells a convergent central integrator of inhibitory regulation of colonic motility. We will first clarify the tissue level responses mediated by sympathetic neurotransmission and inhibitory neuropeptides that can be attributed to mechanisms expressed uniquely by PDGFRa+ cells. Preliminary data clearly show direct sympathetic innervation and inhibitory effects of PDGFRa+ cells powerful enough to halt propulsive contractions in the colon. This is an exciting new concept of how stressful conditions might radically alter bowel habits through PDGFRa+ cells. Our findings suggest that any stimulus coupled to Ca2+ transients in PDGFRa+ cells will activate small conductance Ca2+-activated K+ channels and initiate powerful hyperpolarization and inhibitory influences on the SIP syncytium. We will use cutting edge Ca2+ imaging techniques, including cell-specific optogenetic sensors, to better understand the cells and sequence of events that occurs in peptidergic and sympathetic inhibitory responses mediated by PDGFRa+ cells. Finally, in studies of single cells we will utilize electrophysiological and imaging techniques to expand our knowledge of ionic conductances that might be used by PDGFRa+ cells to generate integrated inhibitory regulation. We will also study the role of Ca2+ stores in the responses and how stores are maintained for long term and repetitive inhibitory responses. Completion of the specific aims will provide novel information about an important cell type never been considered a regulatory factor in GI motility. Knowledge of the regulatory mechanisms contributed by PDGFRa+ cells will provide new understanding about factors that generate normal colonic possibly discover new methods for therapeutic management of motility disorders. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page

Public Health Relevance

Intrinsic and extrinsic nerves organize appropriate movements of the GI tract. We are investigating the role of a novel type of cell that is a major contributor to inhibitory regulation of colonic motility. We have found these cells are involved in transducing purinergic, peptidergic and sympathetic inhibitory neurotransmission in the colon and gating the propagation of propulsive contractions along the colon. Mechanisms provided by these cells are fundamental to normal colonic motility. Our studies may provide new ideas for therapeutic regulation of colonic movements and provide relief from functional disorders, such as constipation and diarrhea.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Shea-Donohue, Terez
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University of Nevada Reno
Schools of Medicine
United States
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Shi, Junchao; Ko, Eun-A; Sanders, Kenton M et al. (2018) SPORTS1.0: A Tool for Annotating and Profiling Non-coding RNAs Optimized for rRNA- and tRNA-derived Small RNAs. Genomics Proteomics Bioinformatics 16:144-151
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
Zhu, Mei Hong; Sung, Tae Sik; Kurahashi, Masaaki et al. (2016) Na+-K+-Cl- cotransporter (NKCC) maintains the chloride gradient to sustain pacemaker activity in interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol 311:G1037-G1046
Sanders, Kenton M; Ward, Sean M; Friebe, Andreas (2016) Rebuttal from Kenton M. Sanders, Sean M. Ward and Andreas Friebe. J Physiol 594:1515
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
Sanders, Kenton M; Kito, Yoshihiko; Hwang, Sung Jin et al. (2016) Regulation of Gastrointestinal Smooth Muscle Function by Interstitial Cells. Physiology (Bethesda) 31:316-26
Sanders, Kenton M (2016) Enteric Inhibitory Neurotransmission, Starting Down Under. Adv Exp Med Biol 891:21-9
Peri, Lauren E; Koh, Byoung H; Ward, Grace K et al. (2015) A novel class of interstitial cells in the mouse and monkey female reproductive tracts. Biol Reprod 92:102

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