The enteric nervous system (ENS) is the collection of neurons and support cells that reside in the gastrointestinal (GI tract). The ENS can exert autonomous control over most GI functions including motility. The ENS can accomplish this task because it composed of functionally distinct neuronal classes that release specific neurotransmitters. Therefore there must be unique mechanisms controlling transmitter from functionally distinct classes of neurons. This control may, be accomplished through the selective expression of presynaptic receptors or calcium channels by different classes of neurons and their nerve endings.
Specific aim 1 will test the hypothesis that there are multiple neurotransmitter pools in enteric nerve endings and that the size and mobility of these neurotransmitter pools determine the strength of synaptic transmission at subsets of synapses. These studies will also test the hypothesis that 5-HT4 receptor agonists (drugs that stimulate intestinal motility) facilitate the movement of neurotransmitter from reserve to readily releasable pools.
Specific aim 2 will focus on the functional role of a newly identified calcium channel subtype (R-type channels) in myenteric neurons. These studies will test the hypothesis that R-type channels are localized to the nerve endings of intestinal sensory neurons and that R-type channels mediate calcium entry required for the release of slow excitatory synaptic transmitters from sensory neurons but not for the release of fast or slow excitatory neurotransmitters from interneurons or motorneurons. These studies will also identify the calcium channels mediating release of neurotransmitters from interneurons and motorneurons. Finally, these studies will examine the contribution of R-type channels to neurotransmission underlying peristalsis in vitro.
Specific aim 3 will test the hypothesis that that there are presynaptic nicotinic and P2X receptors on sensory nerve endings in the myenteric plexus. Data from these studies will contribute to our understanding of neuronal control of GI function. It is anticipated that our results will provide new insights into alterations in neural function leading to motility disorders. It is also anticipated that these studies will identify new targets for drugs that can be used to treat GI motility disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057039-06
Application #
6916231
Study Section
Special Emphasis Panel (ZRG1-DIG-C (02))
Program Officer
Hamilton, Frank A
Project Start
1999-09-01
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
6
Fiscal Year
2005
Total Cost
$218,377
Indirect Cost
Name
Michigan State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Rodriguez-Tapia, Eileen S; Naidoo, Vinogran; DeVries, Matthew et al. (2017) R-Type Ca2+ channels couple to inhibitory neurotransmission to the longitudinal muscle in the guinea-pig ileum. Exp Physiol 102:299-313
Galligan, J J; Patel, B A; Schneider, S P et al. (2013) Visceral hypersensitivity in female but not in male serotonin transporter knockout rats. Neurogastroenterol Motil 25:e373-81
France, M; Bhattarai, Y; Galligan, J J et al. (2012) Impaired propulsive motility in the distal but not proximal colon of BK channel ?1-subunit knockout mice. Neurogastroenterol Motil 24:e450-9
Dong, Hua; Wang, Shihua; Galligan, James J et al. (2011) Boron-doped diamond nano/microelectrodes for biosensing and in vitro measurements. Front Biosci (Schol Ed) 3:518-40
Patel, B A; Dai, X; Burda, J E et al. (2010) Inhibitory neuromuscular transmission to ileal longitudinal muscle predominates in neonatal guinea pigs. Neurogastroenterol Motil 22:909-18, e236-7
Devries, Matthew P; Vessalo, Megan; Galligan, James J (2010) Deletion of P2X2 and P2X3 receptor subunits does not alter motility of the mouse colon. Front Neurosci 4:22
Decker, D A; Galligan, J J (2010) Molecular mechanisms of cross-inhibition between nicotinic acetylcholine receptors and P2X receptors in myenteric neurons and HEK-293 cells. Neurogastroenterol Motil 22:901-8, e235
Naidoo, V; Dai, X; Galligan, J J (2010) R-type Ca(2+) channels contribute to fast synaptic excitation and action potentials in subsets of myenteric neurons in the guinea pig intestine. Neurogastroenterol Motil 22:e353-63
Decker, Dima A; Galligan, James J (2009) Cross-inhibition between nicotinic acetylcholine receptors and P2X receptors in myenteric neurons and HEK-293 cells. Am J Physiol Gastrointest Liver Physiol 296:G1267-76
Ren, Jianhua; Zhou, Xiaoping; Galligan, James J (2008) 5-HT4 receptor activation facilitates recovery from synaptic rundown and increases transmitter release from single varicosities of myenteric neurons. Am J Physiol Gastrointest Liver Physiol 294:G1376-83

Showing the most recent 10 out of 15 publications