The purpose of the proposed research is to understand more about the function of the enteric nervous system, and particularly the way in which it controls the motility and absorptive functions of gastrointestinal tract. The experimental approach will be electrophysiological, by making intracellular recordings from neurons lying in the myenteric and submucous plexuses of the guinea-pig small intestine. Three levels of approach are planned. The first is a study of the detailed properties of the individual neurons, particularly their membrane ion channels, their cell surface receptors (particularly for catecholamines and acetylcholine), and their intracellular second messengers which couple receptors to ion channels. The second is an investigation of the way in which the nerve cells are synaptically connected; this will be done by observing the effects of surgical lesions, and by recording from pairs of neurons at the same time. The third approach is to record from single cells in circumstances in which they are more or less intact in the wall of the intestine, and responsive to the physiological synaptic inputs during reflex activity. This may allow us to construct a model for the way in which the nerve cells control peristalsis. The health related significance of this work derives from the directness of its approach to the function of gastrointestinal nerves. The enteric nervous system is involved in primary disease states, and also contributes to the pathophysiology of a wide range of conditions in which it is not primarily involved. These range from peptic ulcer to irritable bowel syndrome, from dysphagia to diabetes. The long term objective of the work is to understand the role of the enteric nervous system and the way in which it contributes to these pathological conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK032979-06
Application #
3231369
Study Section
Physiology Study Section (PHY)
Project Start
1983-04-01
Project End
1986-12-31
Budget Start
1986-04-01
Budget End
1986-12-31
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Piguet, P; North, R A (1992) The inward rectifier potassium conductance in rat basophilic leukemia cells. J Cell Physiol 151:269-75
Shen, K Z; North, R A; Surprenant, A (1992) Potassium channels opened by noradrenaline and other transmitters in excised membrane patches of guinea-pig submucosal neurones. J Physiol 445:581-99
Kavanaugh, M P; Christie, M J; Osborne, P B et al. (1991) Transmitter regulation of voltage-dependent K+ channels expressed in Xenopus oocytes. Biochem J 277 ( Pt 3):899-902
Barajas-Lopez, C; Surprenant, A; North, R A (1991) Adenosine A1 and A2 receptors mediate presynaptic inhibition and postsynaptic excitation in guinea pig submucosal neurons. J Pharmacol Exp Ther 258:490-5
Hurst, R S; Busch, A E; Kavanaugh, M P et al. (1991) Identification of amino acid residues involved in dendrotoxin block of rat voltage-dependent potassium channels. Mol Pharmacol 40:572-6
Galligan, J J; North, R A (1991) Opioid, 5-HT1A and alpha 2 receptors localized to subsets of guinea-pig myenteric neurons. J Auton Nerv Syst 32:1-11
Kavanaugh, M P; Varnum, M D; Osborne, P B et al. (1991) Interaction between tetraethylammonium and amino acid residues in the pore of cloned voltage-dependent potassium channels. J Biol Chem 266:7583-7
Christie, M J; North, R A; Osborne, P B et al. (1990) Heteropolymeric potassium channels expressed in Xenopus oocytes from cloned subunits. Neuron 4:405-11
Tatsumi, H; Costa, M; Schimerlik, M et al. (1990) Potassium conductance increased by noradrenaline, opioids, somatostatin, and G-proteins: whole-cell recording from guinea pig submucous neurons. J Neurosci 10:1675-82
Galligan, J J; North, R A (1990) MK-801 blocks nicotinic depolarizations of guinea pig myenteric neurons. Neurosci Lett 108:105-9

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