June 4, 1998 NEW YORK, NY, May 28, 1998 -- Normal functioning of the heart and the brain depends upon specialized cells that act as pacemakers. These cells generate rhythmic, spontaneous electrical impulses that can control muscle activity, certain automatic functions such as breathing, and behavioral states, including arousal from sleep. Inappropriate pacemaker activity can lead to both inherited and acquired cardiac arrhythmias, and may also underlie various neurological disorders. Two laboratories of the Howard Hughes Medical Institute and the Center for Neurobiology and Behavior at Columbia University report in the May 29, 1998, issue of Cell the discovery that the pacemaker activity in both the heart and the brain is mediated by a common family of novel genes.
The genes, from mouse and human, encode a family of protein ion channels in the cell membranes of nerve and/or muscle cells that help generate pacemaker activity. The channels open and close in response to physiological stimuli and allow the positively charged ions sodium and potassium to cross the cell membrane and initiate an electrical impulse. Specifically, these pacemaker channels keep a stimulated cell active when it would otherwise return to a resting state.
"A pacemaker channel senses that a cell has just fired and tells it that it can't rest, it has to fire another action potential," says Steven Siegelbaum, Ph.D., professor of pharmacology at Columbia University College of Physicians & Surgeons and a Howard Hughes investigator. He and Eric Kandel, M.D., University Professor and senior investigator at the Howard Hughes Medical Institute at Columbia, head the two collaborating labs. Bina Santoro, a postdoctoral fellow in Dr. Kandel's laboratory, and Gareth Tibbs, a postdoctoral fellow in Dr. Siegelbaum's laboratory, led the team that identified the pacemaker channel genes. Other members of the research team are David Liu, Huan Yao, and Dusan Bartsch.
The researchers reported the first member of this gene family in December 1997.
A clue to the nature of the protein it encodes was that it included two regions that are key features of known pacemaker channels. But the researchers couldn't be certain that the gene encoded a pacemaker channel, because it is expressed only in the brain, not in the heart. In addition, they didn't know precisely how the channel functions. The researchers now report, that one of the five related genes described in Cell encodes ion channels with properties identical to those of the known pacemaker channel of the brain and are very similar to pacemaker channels in the heart. In fact, three of the related genes described in Cell are found in the heart as well as the brain. The new work not only confirms that the gene reported in December specifies a pacemaker channel, but also gives the researchers several new tools with which to study the effects of abnormally functioning pacemakers on health.
Identifying the genes that control pacemaker activity in the heart and brain should make it possible to develop screening tests for cardiac and neurological disorders that result from mutations or other biochemical changes that cause inappropriate activation of these channels. For example, in the heart ventricles, which pump blood, pacemaker channels are normally silent. "But during heart disease, for reasons that we do not understand, the ventricles can act as their own pacemaker. This can have dire consequences, such as cardiac arrhythmias," says Dr. Siegelbaum.
Potential therapeutic applications of the gene family discovery are diverse. "In the brain, epilepsy may result from excess use of the pacemaker channel. Suppressing this activity might decrease the tendency to have a seizure," suggests Dr. Kandel. Altering pacemaker channel function might also one day be used to manipulate levels of awareness. "The 'burst' activity that pacemaker channels generate is important for the state of arousal. Conceivably by activating this current, one might increase alertness, improve attention in the elderly, or enhance cognition under other circumstances," Dr. Kandel adds.
And because several genes control pacemaking, determining where and when they function will provide information to guide researchers in developing drugs that will target specific abnormalities of the brain and heart. "At this point, the field is in its infancy," cautions Dr. Siegelbaum.
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