May 29, 1998
Researchers Discover Molecular Pacemakers for Heart and Brain
A single family of genes is responsible for pacemaker activity in
both heart and brain, say researchers from the Howard Hughes Medical
Institute at Columbia University.
"These genes encode a family of pacemaker ion channels," says Hughes
investigator Steven
Siegelbaum of Columbia University. "With the identification of
these genes it should now be possible to devise genetic screens to
identify their role in various inherited cardiac diseases and
neurological disorders."
Ion channels are specialized proteins in the membranes of nerve and
muscle cells that open and close in response to physiological stimuli.
These channels allow sodium and potassium ions to cross the cell
membrane and initiate an electrical impulse. Siegelbaum's laboratory
discovered the gene family and characterized their function in
collaboration with the laboratory of Hughes investigator Eric Kandel, also at
Columbia University. Their results are published in the May 29, 1998,
issue of Cell.
Pacemaker cells generate the rhythmic, spontaneous electrical
impulses that power the heart and brain. In the heart, pacemaker
activity regulates the heartbeat. In the brain, pacemakers have a wider
range of responsibilities, including control of particular behavioral
states, including arousal during the sleep-wake cycle; the binding
together of the components of perception; and certain rhythmic
autonomic functions, such as respiration.
Defective pacemaker activity can lead to inherited or acquired
cardiac arrhythmias and may also underlie certain neurological
diseases. The existence of pacemakers in the brain and the heart raises
the question of whether pacemakers share a common molecular basis. In
1997, Kandel's laboratory discovered the first member of the pacemaker
gene family, although they were not completely certain of the protein's
true identity at the time.
There were a few obstacles to clear before the group could be sure
that they had indeed cloned a pacemaker: First, the gene was present
only in brain, and Kandel's team knew that true pacemakers are found in
both heart and brain tissue. Second, they had no idea about the
functional properties of the protein coded for by the gene,
bcng-1. Based on the sequence of the gene, however, they
suspected that they had cloned a heretofore elusive pacemaker ion
channel.
The break came when Kandel's team, which included Bina Santoro and
Dusan Bartsch, in collaboration with Siegelbaum's laboratory, which
included Gareth Tibbs, David Liu and Huan Yao, found five additional
closely related genes in mice and humans. The teams showed that three
of the five genes are expressed in both brain and heart. The
HHMI/Columbia researchers also showed that one of the genes codes for
an ion channel with electrical properties identical to native brain
pacemaker channels and similar to cardiac pacemaker
channels—providing proof that the genes are fundamental for
pacemaking.
The discovery of this new family of genes is likely to aid
understanding of a wide range of cardiac and neurological diseases that
involve faulty ion channels. "The knowledge of the structure of these
ion channels, especially knowing that there are subtle differences
between heart and brain pacemaker channels, is likely to aid in the
development of new drugs for treating heart arrhythmias and
neurological diseases," said Kandel.
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