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Michael Tymianski talks with
ScienceWatch.com and answers a few questions about
this month's Fast Moving Front in the field of Molecular
Biology & Genetics. The author has also sent along
an image of his work.
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Article: A key role for TRPM7 channels in anoxic
neuronal death
Authors: Aarts, M;Iihara, K;Wei, WL;Xiong, ZG;Arundine,
M;Cerwinski, W;MacDonald,
JF;Tymianski,
M
Journal: CELL, 115 (7): 863-877 DEC 26 2003
Toronto Western Hosp, Res Inst, Toronto, ON M5T 2S8,
Canada.
Toronto Western Hosp, Res Inst, Toronto, ON M5T 2S8,
Canada.
Univ Toronto, Dept Physiol, Toronto, ON M5S 1A8,
Canada.
Univ Toronto, Dept Surg, Toronto, ON M5S 1A8, Canada.
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Why do you think your paper is highly
cited?
This paper is of interest to a wide audience. Most importantly, it provides
the first strong evidence that excitotoxicity, the process by which the
excitatory neurotransmitter glutamate causes neuronal cell death in stroke,
is not the chief mechanism responsible for anoxic neuronal death. The
findings provide mechanistic evidence which demonstrates that treating
exictotoxicity is insufficient to prevent the death of anoxic neurons
because TRPM7, a member of the Transient Receptor Potential superfamily of
proteins, triggers parallel death mechanisms that occur independently of
excitotoxicity.
The results may explain why attempts at treating stroke solely using
anti-excitotoxic strategies (glutamate receptor antagonists) have failed.
Moreover, the results provide a new target, TRPM7, which may be a key to
treating to anoxic death. Furthermore, although TRPM7 can trigger anoxic
neuronal death, it is also expressed in other tissues. Consequently, TRPM7
may participate in broader ischemic mechanisms, in tissues both within and
outside the CNS. Thus TRPM7 may be of interest to all those interested in
tissue ischemia.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
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image & details
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To our knowledge, ours was the first paper to use RNA interference in fully
differentiated non-dividing postmitotic neurons to suppress the expression
of a protein.
Would you summarize the significance of your paper
in layman's terms?
The paper describes a previously unappreciated cell death mechanism caused
by a protein, TRPM7, which triggers brain cell death when the cells are
deprived of oxygen and glucose. The lack of oxygen and glucose is what
happens in strokes, a leading cause of death and disability in Western
society. The discovery of the importance of TRPM7 is causing the death of
brain cells may explain why previous attempts at preventing the damaging
effects of strokes was unsuccessful, and provide a potential target for
future drug treatments of strokes.
How did you become involved in this research and
were any particular problems encountered along the way?
I am a stroke researcher. When clinical trials of anti-excitotoxic
strategies uniformly failed in the late '90s, I began to re-examine
potential causes for this, including the possibility that other key
mechanisms of ischemic damage might have been overlooked. We began by
reproducing the original experiments which demonstrated that blocking
excitotoxicity in cultured neurons inhibited cell death caused by
oxygen-glucose deprivation (OGD). We then extended the duration of OGD and
found that, even when excitotoxicity was blocked, the neurons still died
(in prolonged OGD). The challenge was to discover why.
We performed various experiments for about two years, but with little
success in narrowing down the mechanism, other than to discover that it
involved an unknown ion conductance (as determined using
electrophysiological techniques). Then, TRPM7 was cloned, and its
electrophysiological properties resembled very much the cation conductance
(i.e., the ion channel) that we were observing in ischemic neurons.
All we had to do was to find a way to block TRPM7. However, there are no
drugs to do so, and no knockout animals. Therefore, we developed a method
to knock down the expression of TRPM7 using RNA interference, a technique
which had just recently been published. When we did so, the neurons became
very resistant to prolonged OGD, confirming a key role for TRPM7 in anoxic
neuronal death.
Where do you see your research leading in the
future?
Our research defines TRPM7 as an important protein which triggers anoxic
death in cultured neurons. Its role in intact animals is as yet uncertain
when it comes to stroke or to other ischemic problems. There are no viable
knockout animals and no drugs to selectively block TRPM7 in order to test
its relevance in-vivo. Our lab is currently carrying out
experiments in which we are suppressing TRPM7 expression in-vivo
in order to determine its importance in stroke. We are also developing
small molecule inhibitors of TRPM7.
Do you foresee any social or political implications for your
research?
If TRPM7 is the key to treating ischemic brain damage, then our discovery
may lead to better treatments for one of the major causes of death and
disability worldwide.
Michael Tymianski, M.D.,Ph.D.,F.R.C.S.C.
Professor
Departments of Surgery and Physiology
University of Toronto
Senior Scientist
Toronto Western Hospital Research Institute Medical Director
Neurovascular Therapeutics Program University Health Network
Toronto, Ontario, CA
Web ¦
See also
Figure 1:
KEYWORDS: METHYL-D-ASPARTATE; CORTICAL CELL-CULTURE; CATION
CHANNEL; CALCIUM NEUROTOXICITY; RECEPTOR ACTIVATION; RNA INTERFERENCE;
CLINICAL-TRIALS; BRAIN INJURY; NITRIC-OXIDE; ACUTE STROKE.
