LA JOLLA, Calif. H By genetically engineering three of the genesthat encode the calcium-ion channels in neurons, scientists atSibia seek a basis for building better drugs to treat braindisorders.
The report in Friday's issue of Science comes just two monthsafter Sibia, a biopharmaceutical company founded by the SalkInstitute, signed a three-year collaborative research contractwith Eli Lilly & Co. to discover and develop high-specificitycompounds that can stimulate or inhibit neurotransmitterrelease from nerve cells.
If these calcium channels are thought of as exact-changehoppers at highway toll plazas, then the calcium ion is thetoken that opens the barrier, releasing the "vehicle," orneurotransmitter, at the gate.
One of the three proteins the researchers expressed, in humanembryonic kidney (HEK) cells, is a channel subunit that formsthe actual pore, or tunnel, through which the ion traverses thecell membrane. The other two subunits help complete thefunctional channel complex. The researchers deduced theprimary structures of the channel's subunits by characterizingoverlapping complementary DNA sequences from humanhippocampus and basal ganglia brain cells.
At least four main membrane channel subtypes control calciumion traffic into nerve cells, where some types triggerneurotransmitter signals dispatched to synapses. These fourvariants react differently with various drugs. The N-typechannel, which Sibia cloned, opens or closes in response to theintensity of electrical impulses. But unlike the other channeltypes, it shuts down permanently when exposed to conitoxin,the venom of a sea-going, fish-hunting snail, Conus geographus.The transfected HEK cells bind conitoxin with high affinity.
"Blocking the N-type, voltage-regulated, conitoxin-sensitivecalcium channel on a neuron that releases acetylcholineneurotransmitter can affect the activity of those neurons," saidSibia's vice president of research, Michael M. Harpold, thesenior author of the Science paper.
"There is highly speculative evidence that the N-type channelmay have pharmacological activity in managing pain, stroke or,say, Parkinson's disease," Harpold told BioWorld. "Parkinson'sreflects a lack in the brain of the neurotransmitter dopamine,"he said. "Perhaps its level could be maintained by controllingcalcium-ion entry to the neuron."
Existence of Channel Established
Harvard University neurobiologist Bruce P. Bean said, "Themain significance of their cloning and expressing the N-typechannel is that it establishes the real existence of this channel,which is unique to neurons." For practical purposes, Beanadded, "it offers a new opportunity for developing a new classof calcium-blocking drugs that may be selectively active in thenervous system."
The new molecular handle on calcium-ion channels grasped bythe Sibia team might have its first application in screeningdrugs, and may later be used to design compounds for specifictherapeutic applications. "The present difficulty in screeningcompounds is that they tend to interact with more than onechannel subtype," said Harpold. "The problem has been todetermine their selective specificity for different types ofchannel.
"We can express the relevant gene in individual cells growablein culture H say, N-type alone," he said. "That way, we canstudy each subtype in isolation and determine if a given drugcan enhance or block activity, then set up a differential screen."
The fact that the different channel types don't react to a givendrug in the same way presents us with a real opportunity,"Harpold continued. "It should be possible to develop drugsspecific for each type, thus avoiding the side-effects cause byless-specific drugs. It's the first practical step toward thinkingabout rational drug design."
-- David Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.