By David N. Leff
Inside your skull, and tailing down your backbone, nestles the central nervous system - a sort of close-up and personal Internet. Its modem, if you will, is an array of neurotransmitters, each operating at its own baud - or rather, millisecond - speed. They transmit the infinity of brain communications by which the animal world lives and dies.
Like Internet servers and bookmarks, neurotransmitters subserve varying functions. For example, GABA - gamma-aminobutyric acid - transmits "stop" or "slow" signals that damp down excitation and anxiety. Other neurotransmitters, such as dopamine and serotonin, influence mood and sleep. Then there's glutamate. It spurs rather than allays excitation, and nudges the brain into high alert, so it can carry out the computations that underlie cognition, memory, sensory perception and most other basic brain activities. Switched to "go" mode, glutamate sends rapid-fire signals needed, say, for vision and learning.
Neurotransmitters are hard drives that carry chemical messages broadcast by one nerve cell, targeting another. A single neuron releases thousands of glutamate molecules, triggering a response in a neighboring cell, which in turn prompts yet another cell to relay that reaction, all at millisecond speed.
While created inside a neuron, neurotransmitters are pumped into synaptic vesicles, tucked into the cell's terminal, or nose cone. These vesicles, tiny bubble-like bags or sacs, then indirectly jump the gap - the synapse - separating the far end of one long neuronal axon from the next in line of signal transmission.
A nerve cell, when activated, sends an electrical impulse down its axon to that fiber's terminal. That impels a vesicle on duty to migrate to, and fuse with, the terminal's surrounding membrane. This opens a conduit that propels the neurotransmitter into the synaptic cleft between neurons. Then, diffusing across that gap, the neurotransmitters bind to waiting receptor proteins on the opposite shore - the target cells, which thus pick up the relayed message.
This traditional, textbook chapter on neurotransmission 101 had one missing section: What force or factor actually transports the chemical messenger on its long, synapse-jumping trajectory to the far-end scene of its reception and action? That elusive puzzler has been scratching the heads of neuroscientists for decades.
Not Phosphate Transport After All
One of their number is neurologist and physiologist Robert Edwards, at the University of California School of Medicine in San Francisco. After years of research, he and his co-workers came up with a glutamate transporter molecule that proved neat, plausible - and not entirely right. Others had originally named that protein "brain-specific inorganic phosphate transporter," but Edwards recently discovered that this steed carried a quite different load. Now he has re-dubbed that neurotransmitter-pumping molecule "vesicular glutamate transporter," or VGLUT1.
The UCSF team reports its finding in today's issue of Science, dated August 11, 2000, in a paper titled: "Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter." Edwards is its senior author.
"The discovery of the glutamate transporter," he told BioWorld Today, "represents a major missing component that people have sought for a long time. The finding's importance," he added, "resembles that of the discovery of glutamate receptors - the proteins that respond to that neurotransmitter on target cells. Our finding represents the flip side - the release of glutamate."
"I think that it's quite novel," Edwards observed, "in the sense that there are a lot of drugs aimed at interfering with excitatory synaptic transmission. Some are drugs aimed at receptors. And there's an effort that we haven't heard much about, looking for drugs that interfere with the release of glutamate, which is a major excitatory neurotransmitter.
"So what we're doing here," he went on, "is providing another drug target for the protein that pumps glutamate into synaptic vessels. So this is a great drug target to interfere with the basic process of synaptic transmission.
Edwards noted in particular, "In this paper we described our functional characterization of one of the two isoforms of this transporter gene, which reportedly has a different function. We presume that we could inhibit the other one without having quite the dramatic effect of inhibiting both."
He envisions "a variety of clinical uses where you would want to shut down synaptic transmission. For example, in the case of someone who had refractory seizures - status epilepticus. It's very difficult to control their seizures in an acute situation in the hospital. Having a medicine like this might give such a patient a very powerful way of controlling that condition.
"Similarly, taking a drug at a dose that did not inhibit this transporter 100 percent could be enough to keep people who are on the borderline of having seizures from getting them. On the other hand," he continued, "if we had a peripherally active version of this drug, which didn't get into the brain so well, it might be quite good in the treatment of pain."
First Catch Your Compound
Edwards broadened the therapeutic potential to include "neurodegenerative diseases - Alzheimer's, Parkinson's and so on, as well as more acute conditions like stroke. In all of these there's evidence of an excess of glutamate. Particularly in motor neuron disease - amyotrophic lateral sclerosis - there's been a lot of discussion in recent years suggesting that glutamate contributes to the degeneration of brain cells.
"Alternatively," he suggested, "measured release of glutamate from certain neurons could improve learning, memory and cognition."
Edwards made the point that "before contemplating human trials, we first need to come up with a drug. Unlike many other neurotransmitter transporters - for which there clearly were already drugs, like Prozac for serotonin- in this case there are no potent compounds that can even get across the plasma membrane of the cell, let alone get into an animal taken systemically. We'd love to develop drugs like that." Edwards is "talking to a pharmaceutical company about developing such a drug." And he concluded, "We should hopefully have filed a provisional patent in the last week or two."