March 18, 2002
Relative of Snake Venom Toxin May Aid in Understanding Nicotine Addiction
Scientists have found that a protein resembling snake venom
neurotoxin modulates the sensitivity of specific receptors in the brain
that are targets of nicotine, the primary addictive drug in tobacco.
The researchers say that the protein, lynx1, may be a new tool with
which to probe how nicotine and other drugs activate “pleasure
centers” of the brain.
Although studies of lynx1 and other members of this intriguing
“prototoxin” protein family are still in the early stages,
the researchers say they may help in understanding nicotine addiction
or possibly human genetic diseases caused by defective prototoxins.
Howard Hughes Medical Institute investigator Nathaniel
Heintz and his colleagues Inés Ibañez-Tallon and
Julie Miwa at The Rockefeller University and colleagues at The Mayo
Foundation and Columbia University reported in the March 14, 2002,
issue of the journal Neuron that lynx1 is an interesting new
modulator of nicotinic acetylcholine receptors.
Julie Miwa, a member of Heintz’s laboratory and co-author of
the Neuron article, first discovered lynx-1 in 1999. The
discovery was especially intriguing, said Heintz, because it confirmed
that mammals harbored a natural, or “endogenous,” protein
resembling snake venom that could affect the nervous system. At the
time the discovery was made, such an assumption was scientifically
risky, said Heintz.
“It was an appealing hypothesis that there might be an
endogenous neurotoxin-like molecule that regulated some sort of
receptor in the nervous system,” said Heintz. “But Julie
was very, very brave to pursue this gene and its protein product on
such a flimsy basis.”
Miwa’s initial work showed that lynx1 was concentrated in the
nervous system. Additional studies in collaboration with
Ibañez-Tallon showed that lynx-1 altered the function of
nicotinic acetylcholine receptors. Acetylcholine is a neurotransmitter
that helps to activate muscles and causes them to contract.
The discovery of lynx1 had potential clinical importance since
nicotine is known to increase the level of the neurotransmitter
dopamine, which in turn produces pleasurable effects in the brain.
Following up on Miwa’s work, lead author of the Neuron
paper, Inés Ibañez-Tallon, used antibodies specific to
lynx1 to reveal in mice that the protein was closely associated with
the nicotinic acetylcholine receptors in neurons.
Ibañez-Tallon then performed more detailed studies of the
function of lynx1 by engineering frog eggs, called oocytes, to produce
both lynx1 and nicotinic acetylcholine receptors. “By studying
the oocytes, Inés found that lynx1 directly modified nicotinic
receptors – an important finding because physiologists had told
us they weren’t really sure that a membrane-bound molecule like
lynx-1 could even access the receptor,” said Heintz. “That
finding really stimulated us to do an in-depth analysis of how lynx1
changed the properties of the receptors. She further showed that lynx1
had a dramatic effect on enhancing desensitization of the receptors to
acetylcholine, and it did so by directly binding to the
receptors,” he said.
Co-author Steven Sine and colleagues at The Mayo Foundation
performed electrophysiological studies of the effects of lynx1 in
cultured human cells, and discovered that lynx1 affected the electrical
conductance of the receptors.
“Steve’s findings revealed that lynx1 modulates this
receptor in a different way than other known modulators,” said
Heintz. Since nicotinic acetylcholine receptors are also expressed on
immune cells, the prototoxin family that includes lynx1 might have
broad regulatory roles in both the immune and nervous systems, he
added.
“It will be very interesting to find out if this class of
molecules in the nervous system just modulates neurotransmitter
receptors, or whether they regulate other cell surface receptors. We
really don’t know yet,” said Heintz.
Heintz and his colleagues are planning additional studies of the
prototoxin gene family in mice. They have disrupted the gene for lynx1
and are studying what effects the loss of the protein will have.
“Although we can’t say much about these effects at this
early stage, clearly this family of proteins is physiologically
important,” he said. Heintz noted, for example, that more work is
needed to determine whether lynx1 or its family members will be useful
drug targets in treating nicotine addiction.
But there’s hope that further studies of the prototoxins in
mice could lead to discovery of genetic disorders caused by mutations
in these genes. “Once we understand the basic functional roles of
the prototoxins in mice, we can proceed to explore whether prototoxin
genes might be mutated in human disease. We will be able to obtain much
more functional information in humans, because we can more readily
detect any subtle abnormalities in people with mutations in a
prototoxin gene,” he said.
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