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Abstract
Studies on the pathogenesis of disease in cholera have aided in the elucidation of
the normal mechanisms of signal transduction by hormones and neurotransmitters. The
abnormalities in fluid and electrolyte flux result from secretion by V. cholerae of cholera toxin or choleragen. The toxin increases intracellular cyclic AMP by activating
adenylyl cyclase. Activation results from the toxin-catalyzed transfer of ADP-ribose
from NAD to a stimulatory component of the cyclase system that is regulated by guanine
nucleotides and activated after ADP-ribosylation. The regulatory protein, known as
GS, is one member of a family of G proteins. These G proteins couple cell surface receptors
for hormones and neurotransmitters to their intracellular effectors; they consist
of three subunits, α, β, and γ, with the α subunit of ~40 kd possessing the guanine
nucleotide-binding site. The proteins are activated by GTP; hydrolysis of GTP by a
GTPase activity intrinsic to the protein results in the formation of GDP and the inactivation
of the protein. Receptors, in the presence of agonist, facilitate the exchange of
GDP for GTP, and thus promote activation of the G protein. These G proteins are involved
in the regulation of multiple pathways such as ion flux, visual excitation, and phospholipid
turnover.
The toxin-catalyzed ADP-ribosylation reaction is enhanced by a guanine nucleotide-binding
protein known as ARF. This 20 kd protein, in the presence of GTP but not GDP, serves
as an allosteric activator of the toxin, increasing its ability to catalyze the ADP-ribosylation
of GS. Because both the allosteric activator of the toxin and the toxin substrate are G
proteins, it appears that a G protein cascade may be responsible for the activation
of adenylyl cyclase by toxin.
Animal tissues contain enzymes that, like cholera toxin, catalyze ADP-ribosylation
reactions, as well as enzymes that remove the ADP-ribose moiety. The physiologic function
of these proteins has not been defined. Some evidence is consistent with a role in
the signal transduction process.
Abbreviations:
ADP (adenosine diphosphate), AMP (adenosine monophosphate), App(NH)p (adenylyl imidodiphosphate), ARF (ADP-ribosylatton factor), CTA1 (the cholera toxin A1 protein), DMPC (dimyristoyl phosphatidylcholine), Ga and Gβγ (the α and βγ subunits of the G protein), GDPβS (guanosine 5′-0′-[β-thio]diphosphate), G1 (the inhibitory G protein of the cyclase system), GM1 (galactosyl-N-acetyl-galactosaminyl-(N-acetylneuraminyl)galactosylglucosylceramide), GMP (guanosine monophosphate), Go (a G protein possibly involved in the regulation of ion flux), Gpp(NH)p (guanylyl imidodiphosphate), G protein (guanine nucleotide-binding protein), Gs (the stimulatory G protein of the adenylyl cyclase system), Gt (transducin the G protein involved in the visual excitation system), GTPγS (guanosine 5′-0-[γ-thio]triphosphate), HPLC (high-performance liquid chromatography), Ko (activation constant), Km (Michaelis-Menten constant), NAD (nicotinamide adenine dinucleotide), SDS (sodium dodecyl sulfate), Vmax (maximum velocity)To read this article in full you will need to make a payment
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signal-transducing proteins and those of bovine retinal rod cell transducing proteins are identical.Article info
Publication history
Accepted:
October 24,
1988
Received in revised form:
October 21,
1988
Received:
September 16,
1988
Identification
Copyright
© 1989 Published by Elsevier Inc.
