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Rodbell knew
that a number of different hormones
increased cAMP (the second messenger) in his purified
fat cells.
Together with postdoctoral fellow Lutz Birnbaumer, he
discovered that each hormone acts through a specialized
receptor,
but all hormones stimulate the same adenylyl cyclase (AC)
molecule. This has been called the "ping pong ball model."
Rodbell thought it unlikely that so many receptors could
interact directly with a single AC molecule. He predicted
that there must be a go-between that carries the signal
from each receptor to the AC molecule. Rodbell used the
word "transducer"
for this go-between, using a term from computer science.
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| To find the transducer that he predicted,
Rodbell turned from fat cells to liver cells. Two things
made this work possible. First, David Neville, of the
National Institute of Mental Health, devised a method
for isolating large amounts of liver cell membranes.
Second, Rodbell developed a technique for measuring the
binding of the hormone glucagon to its receptor in those
membranes.
With the liver cell membranes and a method to test them
in hand, Rodbell and his team (Lutz Birnbaumer, H. Michiel
J. Krans, and Stephen L. Pohl) tested the response of
the cell membranes to the hormone glucagon.
Their experiments proved that a molecule called guanosine
triphosphate (GTP) was necessary for the transmission
of a message from a glucagon-bound receptor to AC. Although
Rodbell did not identify and isolate the transducer, he
proved that it existed, was dependent on GTP, and was
an integral feature of all receptors that increase the
activity of AC. Alfred G. Gilman shared the Nobel Prize
with Rodbell for finding the transducer, called the "G-protein."
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| Rodbell also developed strong evidence
for a second type of transducer—one linked to receptors
that inhibit functions within the cell. He accurately
predicted that other pairs of transducers and receptors
would be found that regulate molecules other than AC.
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Ping
Pong Ball Model
Each hormone acts through
a specialized receptor, but all hormones stimulate
the same adenylyl cyclase (AC) molecule. |
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3-Part
Transducer Model
Rodbell's model of signal
transduction: The signal from the hormone is transduced
and amplified inside the cell. |
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Typed
protocol for AC assay
solutions (carbon copy)
In April 1966, Rodbell typed
this protocol, which describes the first measurements
of AC done in his laboratory. |
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Hand-sketched
graph #3
Rodbell drew this graph on
January 5, 1970. These results culminated a series
of experiments that showed for the first time that
hormone receptors were regulated by a transducer
that required GTP.
In this experiment, glucagon was first bound to
its receptor on liver membranes. Then different
concentrations of GTP (shown on
the curves) were added. The data showed that very
low concentrations of GTP caused glucagon to dissociate
from the receptor. |
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