Calcium Is Spark Of Life, Kiss Of Death For Nerve Cells

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Calcium Is Spark Of Life, Kiss Of Death For Nerve Cells

http://www.sciencedaily.com/releases/2007/03/070301102758.htm

Oregon Health & Science University research shows how calcium

regulates the recharging of high-frequency auditory nerve cells

after they've fired a burst of signals, and it may have implications

for neurological disorders.

The study by scientists at OHSU's Vollum Institute and the

University of Arkansas for Medical Sciences, which appears in the

current issue of the journal Nature Neuroscience, shows that calcium

ions play a greater role in keeping in check the brain's most

powerful circuits, such as those used for processing sound signals,

than previously thought.

A better understanding of that role could someday help prevent the

death of neurons behind some diseases of the brain and spinal cord,

such as stroke and multiple sclerosis, the scientists say.

The research, led by postdoctoral fellow Jun Hee Kim, Ph.D., and her

advisor, Henrique von Gersdorff, Ph.D., both scientists at the

Vollum Institute, found that calcium tempers the activity of a high-

throughput sodium pump, located in the plasma membrane covering

nerve endings, that controls how quickly and accurately a nerve cell

continues firing after an initial burst of spiking activity.

" What's happening in the brain is you have all these action

potentials (spikes) that are firing - the action potential is the

way you transmit information quickly from neuron to neuron - and

when you have an action potential, you have an explosive influx of

sodium ions into the cell, " von Gersdorff said. " As a result, the

cell is depolarized and it needs to be quickly repolarized. "

To repolarize a cell so it can continue firing, and do so accurately

and at high-input frequencies, the sodium pump ejects three

positively charged sodium ions and imports two positively charged

potassium ions. The net result is one positive charged is expelled

from the cell, causing a hyperpolarization of the cell's membrane

potential.

Quick repolarization of the nerve cell is essential. Mature auditory

nerve cells fire at frequencies that are 10 to 100 times higher than

most high-frequency cells in the brain - 1 kiloHertz, or 1,000

Hertz. Most brain synapses, the space between nerve cells through

which impulses are transmitted and received, begin failing beyond 10

Hertz.

" In the last few years, we have been studying high-frequency firing

cells in the auditory part of the brain. We found that these cells

and nerve terminals are amazing because they can fire at 1,000 Hertz

without failures and with high precision, " von Gersdorff said. " That

discovery in our lab prompted us to ask the question: How is it that

these nerve cells can handle all this high-frequency firing? "

Enter calcium, which, by inhibiting the activity of the sodium pump,

regulates signal firing, and may conserve energy and keep the high-

frequency cells from burning out. But calcium in high levels within

a nerve cell can be toxic, so the researchers discovered another

purpose for the sodium pump: powering a protein located on the nerve

terminal membrane called the sodium-calcium exchanger, which removes

the calcium and replaces it with sodium. That action, in turn,

triggers the sodium pump, and so on.

The sodium-calcium exchanger " can import high concentrations of

sodium from outside the cell, and it uses the gradient of low

internal sodium in the cell as a form of energy to get rid of

calcium. That energy comes, ultimately, from the sodium pump and its

use of ATP, the cells' major fuel, " von Gersdorff explained. The

pump is " always keeping sodium concentration in the neuron low and

that allows the sodium-calcium exchanger protein to constantly

exchange sodium for calcium. "

Otherwise, if allowed to get too high within the cell, the calcium

shuts down the sodium pumps, creating a " vicious loop, " von

Gersdorff said.

" You then get a simultaneous build-up of calcium and sodium in the

cell, and it's 'Goodbye to your neuron.' It goes at some point into

an irreversible cycle of death, " he said.

One potential therapeutic approach to preventing cell death caused

by increasing calcium levels is making the sodium pump more

insensitive to calcium. A potential new drug, for example,

could " help the neuron to keep extruding sodium so it can help the

sodium-calcium exchanger get rid of calcium, thereby not allowing

calcium to reach toxic levels, " von Gersdorff said.

For the time being, von Gersdorff's lab will continue studying how

calcium regulates the sodium pump.

" Our hope is that these basic, fundamental issues will eventually

lead to therapeutic strategies that alleviate neuronal damage from

ischemia and stroke, " he said.