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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK091336-02
Application #
8692557
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Carrington, Jill L
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Reno
State
NV
Country
United States
Zip Code
89557
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Baker, Salah A; Hennig, Grant W; Ward, Sean M et al. (2015) Temporal sequence of activation of cells involved in purinergic neurotransmission in the colon. J Physiol 593:1945-63
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Blair, Peter J; Rhee, Poong-Lyul; Sanders, Kenton M et al. (2014) The significance of interstitial cells in neurogastroenterology. J Neurogastroenterol Motil 20:294-317
Kurahashi, Masaaki; Mutafova-Yambolieva, Violeta; Koh, Sang Don et al. (2014) Platelet-derived growth factor receptor-α-positive cells and not smooth muscle cells mediate purinergic hyperpolarization in murine colonic muscles. Am J Physiol Cell Physiol 307:C561-70
Peri, L E; Sanders, K M; Mutafova-Yambolieva, V N (2013) Differential expression of genes related to purinergic signaling in smooth muscle cells, PDGFRα-positive cells, and interstitial cells of Cajal in the murine colon. Neurogastroenterol Motil 25:e609-20
Baker, Salah A; Hennig, Grant W; Salter, Anna K et al. (2013) Distribution and Ca(2+) signalling of fibroblast-like (PDGFR(+)) cells in the murine gastric fundus. J Physiol 591:6193-208

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