February 2, 1995: Vol26n15: Researchers' report on gene clone has implications for development of

By ELLEN GOLDBAUM
News Bureau Staff
Pharmacologists at UB have cloned the gene that codes for a
calcium-channel subunit in fruit flies and have discovered that the
alpha-1 subunit bears a remarkable resemblance to one found in the rat
brain. The findings, to be published in the February Journal of
Neuroscience, may have immediate implications for the development of
species-specific pesticides and new cardiovascular treatments.
	They also are important in increasing the understanding of the
variety of roles calcium channels play in vertebrates.
	Support for the research came from Rhone-Poulenc, the French
chemical company, the National Institutes of Health and the NYS
chapter of the American Heart Association.
	"Calcium channels from insects have different pharmacological
properties from those of vertebrates," said Linda M. Hall, professor
of biochemical pharmacology at UB and principal
investigator. "Researchers have postulated that they therefore would
have a very different molecular structure. But our work shows that
they follow the same general architectural plan."
	Calcium channels and the subunit molecules of which they are
made are of interest for various reasons, Hall explained. They are
ubiquitous in cells that process information by sending electrical
signals in species ranging from Paramecium to humans, and they play a
key role in skeletal muscle and heart function and are targets for
numerous cardiovascular drugs. In addition, neuronal calcium channels
are potential targets for neuroprotective agents for use in treating
stroke, ischemia, head injury and other brain trauma.
	Hall explained that calcium channels all have the same general
"job," which is to open up when stimulated to allow calcium into the
cell. "However, the details of when they open up, how fast they open
and close, and which other molecules affect their opening and closing
vary from one channel type to another," she said. "Since different
channel types are found in different types of cells, such as heart,
muscle, or neuronal cells, it would be a distinct advantage to be able
to specifically open or block one type of channel at a time." Each
calcium channel is composed of five subunits, each of which, in turn,
is a single protein molecule.
he fact that the structural similarity of
	the alpha-1 subunit has been conserved across such different
species is a signal to researchers that the subunit and the calcium
channel of which it is part, perform an important function.
	According to Hall, the regions of the protein that are
identical between rats, humans and fruit flies, or Drosophila
melanogaster, identify for scientists the functionally most important
parts of the molecule, which, if altered, would disrupt channel
functions.
	"These sites are most important for understanding how channels
open and close in the brain, which is how the brain sends electrical
signals -- part of our normal thought processes -- from one region to
another," said Hall.
	Companies are interested in developing products, such as drugs
or pesticides, which are specific for certain channel subunits. By
targeting individual subunits that are in flies, for example, and not
in humans, a pesticide could be effective without having a
toxicological impact on humans.
	"We now know which regions of the calcium channel are the same
and which are different between the human and the fly," Hall
said. "For species-specific pesticides, you want to target regions
that are different."
	Now that this channel subunit has been cloned, the researchers
can develop systems for their expression outside the insect in tissue
culture cell lines or in frogs' eggs.
	"By expressing the channels in cell lines where they are not
ordinarily expressed, pesticide researchers like those at
Rhone-Poulenc can set up rapid and simple assays for testing compounds
for insecticidal action against these channels," she said.
	The research also has implications for the development of more
targeted cardiovascular drugs, since the alpha-1 subunit contains the
binding sites for several of them. "One can design more effective
drugs if you can pinpoint the molecular site of each binding
interaction," said Hall.