October 11, 2011 -- A tiny piece of a
critical receptor that fuels the brain
and without which sentient beings cannot
live has been discovered by University
at Buffalo scientists as a promising new
drug target for Alzheimer's and other
neurodegenerative diseases.
The research on the NMDA (N-methyl-D-aspartate) receptor
is being published online Oct. 11 in Nature
Communications.
"This is the first time that this site has been shown to
be useful as a drug target," says Gabriela K. Popescu,
PhD, associate professor of biochemistry in UB's School
of Medicine and Biomedical Sciences and senior author on
the study.
"If we could find a drug that attaches itself to this
site and locks together NMDA receptor subunits, that
would be huge for fighting disability from stroke and
Alzheimer's and other neurodegenerative diseases."
The research focuses on the brain's receptors for the
neurotransmitter, glutamate, which is implicated in
these diseases as well as in other conditions, such as
glaucoma.
The two main glutamate receptors in the
brain are NMDA and AMPA receptors, both of
which play critical roles in human learning
and memory. Both types of receptors are made
of four subunits and within each receptor
these subunits are organized in pairs called
dimers.
Because these receptors are so similar in structure,
Popescu explains, it was assumed that they function in
much the same way.
"But when we altered the dimer interface, the site where
two subunits come together within each pair, we found
that the NMDA receptor works just the opposite of the
way that the AMPA receptor works," Popescu explains.
"Cementing this interface in AMPA receptors leads to
more activity, whereas we found just the opposite to be
true in NMDA receptors."
By locking the subunits together, the UB researchers
were able to achieve a marked reduction in NMDA activity
and, subsequently, a marked reduction in the amount of
calcium that enters neurons in response to the
neurotransmitter glutamate. Calcium overload due to
overactive NMDA receptors is what eventually kills off
neurons, Popescu explains, leading to the symptoms that
occur after a stroke, and in Alzheimer's and other
neurodegenerative diseases.
"The fact that by cross-linking the subunits, we could
so dramatically reduce NMDA receptor activation
demonstrates, for the first time, the tantalizing
possibility that we may be able to develop new therapies
that can much more effectively treat, or even one day
prevent, some of these devastating diseases, like
Alzheimer's and stroke," says Popescu.
And, because each type of NMDA receptor has a slightly
different dimer interface, Popescu explains, this
finding represents a new opportunity for rationally
designing drugs that would preferentially inhibit only a
select population of NMDA receptors in the brain, thus
reducing the possibility of side effects.
Currently, the Alzheimer's drug called Namenda, one of
the only existing pharmaceuticals that inhibit the NMDA
receptor, targets a different site within the receptor.
"If a new drug could be developed to target the dimer
interface, which we discovered to be inhibitory, it
would allow more specific effects than current drugs,"
explains Popescu. "That's because at this particular
interface, the interactions between these subunit
interfaces are more precise than those currently being
targeted."
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Co-authors on the paper are: William F. Borschel and
Swetha E. Murthy, both of whom are doctoral candidates
in the UB Department of Biochemistry, and Eileen M.
Kasperek, senior technician in the department.
Funding for the work was provided by the NIH National
Institute of Neurological Disorders and Stroke.
The University at Buffalo is a premier
research-intensive public university, a flagship
institution in the State University of New York system
and its largest and most comprehensive campus. UB's more
than 28,000 students pursue their academic interests
through more than 300 undergraduate, graduate and
professional degree programs. Founded in 1846, the
University at Buffalo is a member of the Association of
American Universities.
