Glutamate transport and storage in synaptic vesicles

Glutamate plays an important metabolic role in virtually every vertebrate cell. In particular, glutamate is the most common excitatory neurotransmitter in the vertebrate central nervous system. As such, the mechanism by which glutamate is diverted from its normal metabolic activities toward its role as a neurotransmitter has, in recent years, been systematically investigated. In glutamatergic nerve endings, synaptic vesicles accumulate and store a proportion of the cellular glutamate pool and, in response to appropriate signals, release glutamate into the synaptic cleft by exocytosis. Glutamate accumulation is accomplished by virtue of a glutamate uptake system present in the synaptic vesicle membrane. The uptake system consists of a transport protein, remarkably specific for glutamate, and a vacuolar-type H+-ATPase, which provides the coupling between ATP hydrolysis and glutamate transport. The precise manner in which the glutamate transporter and H+-ATPase operate is currently the subject of debate. Recent data relevant to this debate are reviewed in this article. Additionally, pharmacological agents thought to specifically interact with the vesicular glutamate transporter are discussed. Finally, a newly discovered, endogenous inhibitor of vesicular uptake, inhibitory protein factor (IPF), is discussed with some speculations as to its potential role as a presynaptic modulator of neurotransmission.