Inside Salk - October 2009 - page 19

Inside SalkOctober 2009
Alcohol’s inebriating effects may be familiar to
many, but themolecular details of its impact on brain activity remain
amystery. A new study by researchers at the Salk Institute provides a
better understanding how alcohol alters the way brain cells work.
Their findings reveal an alcohol trigger site located physically
within an ion channel protein; their results could lead to the develop-
ment of novel treatments for alcoholism, drug addiction, and epilepsy.
Paul Slesinger
and his team now show that alcohols directly interact
with a specific nook contained within a channel protein. This ion
channel plays a key role in several brain functions associatedwith
drugs of abuse and seizures.
Previous research by Slesinger and his group focused on the neural
function of these ion channels, called GIRK channels. GIRK channels
open up during periods of chemical communication between neurons
and dampen the signal, creating the equivalent of a short circuit.
Having the location of a physical alcohol-binding site important
for GIRK channel activation could point to new strategies for treating
related brain diseases. Using this protein structure, it may be possible
to develop a drug that antagonizes the actions of alcohol for the
treatment of alcohol dependence.
Discovery Roundup
Alternatively, “If we could find a novel drug that fits the alcohol-
binding site and then activate GIRK channels, this would dampen
overall neuronal excitability in the brain and perhaps provide a new
tool for treating epilepsy,” says Slesinger.
Site for Alcohol’s Action in the
Brain Discovered
A tightly controlledsystemof checks
and balances ensures that a powerful tumor
suppressor called p53 keeps a tight lid on
unchecked cell growth but doesn’t wreak havoc
in healthy cells. In their latest study, scientists
at the Salk Institute suggest just how finely
tuned the system is and how little it takes to
tip the balance.
When unprovoked, at least two negative
regulators—the related proteinsMdm2 and
Mdmx—prevent p53 from unleashing its power
to kill. But just slightly increasing the amount of
availableMdmx, which grips p53 and renders it
inactive, the Salk researchers discovered, made
mice remarkably resistant to the harmful effects
Why Some Tumors Don’t Respond to Radiation and Chemotherapy
of radiation but very susceptible to the develop-
ment of oncogene-induced lymphomas.
“Our experiments emphasize how subtle and
precarious the balance is,” says postdoctoral
researcher and first author
Yunyuan V. Wang
“A slight shift of balance and themice survive
the equivalent of Chernobyl but are in big
trouble when an oncogene is activated.”
Their findings could explainwhy some tumors
don’t respond to radiation or chemotherapy, and
provide novel routes for the development of new
anti-cancer therapies.
As a powerful tumor suppressor, p53 turns
on genes that either halt cell division to allow
time for repair of damagedDNA or, when all
rescue attempts prove futile, to prevent cells with
genetic defects from dividing, as this would fuel
the development of cancer. Consequently, before
any tumor cell can start proliferating willfully, it
needs to escape from p53’s iron fist.
“One way or another, p53 function is compro-
mised in all cancers. Either p53 itself ismutated
or there is a problemwith one of the proteins that
regulate p53’s activity,” says the study’s leader
GeoffreyM. Wahl
, a professor in the Gene Expres-
sion Laboratory. “Our hope is that we can develop
small molecule drugs that will activate p53 in
those tumors where it is still functional but inacti-
vated by one of its negative regulators.”
X-ray crystallography revealeda binding site for alcohol in an ion channel.
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