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In anoxia, why can’t humans be more like western painted turtles?

04.04.2005

The right answer could yield better anesthetics, as well as improved stroke and heart attack outcomes – for everyone

For a human, mere minutes without oxygen (called anoxia) resulting from cardiac arrest, cerebral stroke or being trapped under water can lead to profound tissue damage and even death. However a Western painted turtle can survive anoxia for months without apparent tissue damage. Why, and how?

"Key to surviving anoxia is the shutting off of energy-utilizing cellular activities, such as the synthesis of proteins and perhaps most importantly reducing the activity of energy intensive ion pumps," according to Leslie T. Buck, a physiologist at University of Toronto’s Zoology Department. Whereas turtles and many other animals have shutoff mechanisms, humans and many mammals don’t.

"However, basic biochemical pathways are common to almost all species, certainly among reptiles (turtles), fish, birds and mammals," Buck said, adding: "Therefore, the basic signals and pathways that permit anoxia-tolerance in the turtle must also be present in mammals."

In studying the natural mechanisms of anoxia tolerance, Buck’s lab focused on a particular ion channel, the N-methyl-D-aspartate (NMDA) receptor. This receptor/channel is strongly associated with anoxic damage in the mammalian brain by permitting a very large flow of calcium ions into the cell during anoxia. Unlike anoxia-sensitive mammals, this doesn’t occur in the western painted turtle’s brain.

*Paper presentation: "NMDA receptor regulation by mitochondrial KATP channels and adenosine receptors in cortical neurons of the anoxia-tolerant western painted turtle," 12:30 p.m.-3 p.m. Sunday April 3, Physiology 381.3/board #A558. On view 7:30 a.m. - 4 p.m. Others in the research team are Damian Shin and Matthew Pamenter.

Featured topic: Buck is also participating in "Mechanisms of metabolic depression: comparative aspects," Sunday April 3, room 30 B/C beginning at 10:30 a.m. His presentation is scheduled for noon.

Buck is presenting the research at the 35th Congress of the International Union of Physiological Sciences in San Diego, March 31 - April 5, 2005.

New potassium channel blockage short-circuits turtle’s shutoff mechanism

A known protective factor is adenosine, a compound that accumulates in both mammalian and reptile (turtle) brains in response to low oxygen levels. It reduces the inflow of calcium through NMDA receptors during anoxia and is associated with brain protection. "However, our work suggests that adenosine isn’t the only protective factor. Even with the adenosine pathways inhibited, calcium influx in anoxic turtle brain still decreases," Buck noted.

Mathew Pamenter, a graduate student in the lab, had the idea to investigate a relatively newly discovered potassium channel (mitochondrial KATP channel) as a possible regulator of NMDA receptor activity during anoxia. "When this new channel was inhibited, the protective decrease in calcium influx previously observed in anoxic turtle brain didn’t occur," Buck said. "This result indicates that this channel plays a key role in the natural anoxia-tolerance of the turtle and opens a new research direction in this area."

Next steps. Buck said one avenue of investigation is to see whether the potassium channels may be part of an oxygen sensing mechanism, which some believe. "Our ultimate goal is to determine the natural cellular pathways responsible for oxygen sensing and the shutting off of energy consuming processes in the turtle," Buck said. "Then I want to apply this knowledge to human clinical situations, such as improving outcomes of cerebral stroke and cardiac infarct, and the development of better anesthetics."