The neuromuscular apparatus in gastrointestinal (GI) muscles is more complicated than previously understood. Enteric motor nerve terminals make very close contacts with 3 types of cells: smooth muscle cells (SMC), interstitial cells of Cajal (ICC) and flibroblast-like cells (FLC). Both ICC and FLC are electrically coupled to SMC. Thus, signals transduced by ICC and FLC can be conveyed electrically throughout the syncytium of SMC. Considerable study has been directed toward SMC and ICC in the past, but there are few studies that have investigated the function of FLC in GI organs. This project will evaluate the function of FLC in mouse and human GI muscles. FLC are specifically labeled with antibodies for PDGFR-alpha. We have developed and verified a transgenic mouse model with constitutive expression of eGFP in PDGFR-alpha+ cells. We will isolate the PDGFR-alpha+ cells and use patch clamp techniques to study the endogenous conductances expressed by these cells and characterize the effects of enteric neurotransmitters on membrane conductances. Preliminary studies demonstrate a large outward current activated by purine neurotransmitters, and the characteristics and pharmacology of this current will be investigated. SMC and ICC respond to purine transmitters with activation of net inward current. Thus, our data suggest that PDGFR-alpha cells mediate purinergic neural responses in GI muscles. We will investigate the innervation of PDGFR + cells using the fluorescence of Ca2+ dyes. We will also use fluorescence activated cell sorting to purify PDGFR-alpha+ cells and characterize the transcriptome of PDGFR + cells. The effects of losing PDGFR + cells on purinergic responses will also be investigated. These studies will improve our understanding of neural regulation of colonic motility and will possibly provide new targets for therapies for motility and functional GI disorders.

Public Health Relevance

Intrinsic nerves organize appropriate movements of the GI tract. We are investigating the role of a novel cell type that is involved in the inhibitory phase f neural regulation. This project will provide new information about how nerves control GI motility and possibly provide new targets for therapies for GI motility and functional disorders.

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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Greenwel, Patricia
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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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