Rodbell, writing in response to a request for a reprint of one of his articles from the series he published with Stephen L.
Pohl and Lutz Birnbaumer, outlined in this letter some of their thinking on the role of guanine nucleotides in hormone action
at the time the article was printed and how it has evolved since.
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1979-11-30 (November 30, 1979)
Hall, Peter F.
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Medical Subject Headings (MeSH):
Signal Transduction and the Discovery of G-Proteins, 1969-1980
The Glucagon-Sensitive Adenyl Cyclase System in Plasma Membranes of Rat Liver: I. Properties (March 25, 1971)
The Glucagon-Sensitive Adenyl Cyclase System in Plasma Membranes of Rat Liver: II. Comparison Between Glucagon- and Fluoride-Stimulated
Activities (March 25, 1971)
The Glucagon-Sensitive Adenyl Cyclase System in Plasma Membranes of Rat Liver: III. Binding of Glucagon: Method of Assay and
Specificity (March 25, 1971)
The Glucagon-Sensitive Adenyl Cyclase System in Plasma Membranes of Rat Liver: IV. Effects of Guanyl Nucleotides on Binding
of 125 I-Glucagon (March 25, 1971)
The Glucagon-Sensitive Adenyl Cyclase System in Plasma Membranes of Rat Liver: V. An Obligatory Role of Guanyl Nucleotides
in Glucagon Action (March 25, 1971)
I am glad to hear that someone is still interested in an "ancient" paper of mine. That paper, as you know, is one
of the first in a series related to the role of guanine nucleotides in hormone action on adenylate cyclase systems in membranes.
As the first in a series, we naturally followed up many of the questions raised in this study. We know now, for example, that
GTP contaminates both the membrane preparations and is a major contaminant in some commercial preparations of ATP. When these
preparations are cleaned of contaminating GTP, hormone action does not occur without the addition of GTP. Our attempt to settle
the question in the first paper was to incubate the membranes for a period of time prior to assay in order to "digest"
any contaminating GTP in the membrane preparation. That experiment was not really conclusive; nonetheless, Fig. 5 gave us
some feeling that GTP was important if not essential to the action of glucagon. Now we know that GTP and glucagon interact
with separate protein molecules which are joined functionally to give a unit we termed RN (R for receptor, N for nucleotide
regulatory protein). The N unit is responsible for activating adenylate cyclase when liganed with GTP. The receptor seems
to inhibit the ability of N to interact with GTP; binding of the hormone to R relieves this inhibition, allowing GTP to bind
to N. Thus, N becomes activated by GTP and then combines (along with R) with adenylate cyclase to form the activated enzyme.
This, in a grossly simplified form, is the status of the problem after nearly nine years of research. It goes on. Hope you
and the others become interested in the problem. It still fascinates me.