Abstract/Details

Adenine nucleotide regulation of receptor guanylyl cyclases: Application to interrupt Escherichia coli heat-stable entertoxin-dependent signalling mediating secretory diarrhea


1997 1997

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Abstract (summary)

Guanylyl cyclase C (GCC) is a transmembrane receptor implicated in the regulation of intestinal fluid homeostasis. Ligand binding to the luminal receptor domain, activates the intracellular guanylyl cyclase that catalyzes the formation of the second messenger guanosine-3$\sp\prime5\sp\prime$-monophosphate (cGMP). Accumulation of cGMP in the epithelium initiates a cascade of events that culminate in chloride flux, establishment of an osmotic gradient and movement of water into the intestinal lumen. Many pathogenic organisms have evolved specific toxins to induce diarrhea in their hosts to magnify their distribution into the environment. One of these secretory compounds is an E. coli heat-stable enterotoxin (STa) that binds GCC and activates its signalling cascade culminating in secretory diarrhea. Therefore, molecular mechanisms regulating GCC are potential targets for treatment of STa-induced secretory diarrhea.

Kinetic analysis of GCC in native and recombinant systems determined that 2-substituted adenine nucleotides (2-ATP) interact with an intracellular target to inhibit guanylyl cyclase activity by a non-competitive, guanosine-5$\sp\prime$-triphosphate (GTP)-dependent mechanism. High concentrations of GTP, in the absence of 2-ATP, could also inhibit GCC suggesting GTP acts downstream of 2-ATP.

This regulatory pathway was applied to prevent the STa signalling mechanism in intact intestinal epithelial cells and identify a target to prevent intestinal diarrhea. Following conversion to 2-ATP, 2-substituted nucleosides activated the inhibitory pathway and prevented STa-induced cGMP synthesis and electrolyte flux at the guanylyl cyclase step. These studies identify a molecular pathway regulating the receptor guanylyl cyclases, characterize its mechanism and apply it to prevent the molecular process responsible for secretory diarrhea.

Indexing (details)


Subject
Cellular biology;
Anatomy & physiology;
Animals
Classification
0379: Cellular biology
0433: Anatomy & physiology
0433: Animals
Identifier / keyword
Biological sciences; guanylyl cyclase C
Title
Adenine nucleotide regulation of receptor guanylyl cyclases: Application to interrupt Escherichia coli heat-stable entertoxin-dependent signalling mediating secretory diarrhea
Author
Parkinson, Scott James
Number of pages
129
Publication year
1997
Degree date
1997
School code
0272
Source
DAI-B 58/04, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780591395686, 0591395681
Advisor
Waldman, Scott A.
University/institution
Thomas Jefferson University
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
9730323
ProQuest document ID
304399320
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304399320
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