Much as turning the television dial changes what comes into the living room, these brain cells are able to change what they allow in by swapping one kind of channel, or membrane opening, for another. Doing so lets the cells fine-tune their messages and adjust connections within the cerebellum, the brain region that controls fine motor skills.
Although the cells' channel-changing ability has been recognized for a few years, the key players controlling it hadn't been identified. Now, by studying mice, the Hopkins team has identified two proteins, called PICK1 and NSF for short, that help replace channels that let charged calcium ions in with another kind of channel that keeps calcium out. If muscle-controlling nerve cells can do the same thing, forcing the swap might help protect them from a calcium overdose that can kill them in Lou Gehrig's disease.
"We don't know yet whether this happens in muscle-controlling nerve cells, but we're looking into it," says Richard Huganir, Ph.D., professor of neuroscience and a Howard Hughes Medical Institute investigator in Johns Hopkins' Institute for Basic Biomedical Sciences.
So far, no one has really looked for the channel changing in other cells in the brain, he says, in part because the swapped channels are most common in these particular cells in the cerebellum (so-called stellate cells). But Huganir thinks the channel changing is going to be relatively common in the brain.
Whether through channel changing or other, more well-understood ways of fine-tuning its responsiveness, a brain cell's activity level depends on its neighbors, the nerves and other cells that connect to it. Although they don't physically touch, the cell and its neighbor are so close to one another at these connection points, called synapses, that molecules released from one cell travel immediately to the next.
These molecules dock at specific places, or receptors, on the cell and trigger "channels" in the cell's membrane to open. Depending on the receptor and the channel, in will flow sodium, calcium, chloride or other charged atoms that then keep the communication process going.
In the cells in the cerebellum, a channel made of proteins called AMPA receptors, built from subunits called GluR3 and GluR4, is usually found at the synapse. If the cells are shocked with an electric current, within minutes the channels are replaced by ones made of GluR2 and GluR3. After the swap, sodium can still get in, but calcium is kept out.
To learn more about how this takes place, the Hopkins researchers studied brain cells from genetically engineered mice. Through their experiments, the researchers determined that the PICK1 and NSF proteins are both required for the calcium-forbidding channel to move into place at the synapse. Exactly how they help the channels move is still unknown, as is why the cells change their channels.
Part of the answer is likely to be self-preservation: Too much calcium inside nerve cells can kill them. But Huganir points out that calcium does a lot of things inside cells, suggesting that the channel swap might be accomplishing more than just keeping the cell alive. "Calcium turns some processes on, and it turns others off," he says. "My personal belief is that the cells might be doing more than just protecting themselves by keeping calcium out."
In some cases, protection might be enough of a goal. In people with Lou Gehrig's disease, or amyotrophic lateral sclerosis (ALS), some muscle-controlling nerve cells die because too much of the brain chemical glutamate binds to the cells' AMPA receptors, and so too much calcium gets inside. If these threatened nerve cells can swap their calcium-allowing channels for the kind that keeps calcium out, it might be possible to harness that switch to prevent the cells from dying. "But that's a big 'if' at this point," says Huganir.
The researchers were funded by the Robert Packard Center for ALS Research at Johns Hopkins, the National Institute of Neurological Disease and Stroke, and the Howard Hughes Medical Institute.
Authors on the paper are Huganir, Stephanie Gardner, Kogo Takamiya, Jun-Gyo Suh, Richard Johnson, Sandy Yum and Jun Xia, all of Johns Hopkins. Suh is now at the Hallym [sic] University College of Medicine, Chuncheon, Gangwondo, South Korea, and Xia is now at the Hong Kong University of Science and Technology.
Under a licensing agreement between Upstate Group Inc. and The Johns Hopkins University, Huganir is entitled to a share of royalty received by the University on sales of products used in this research. Huganir is a paid consultant to Upstate Group Inc. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.
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