Eric D. Ozkan (1) and Tetsufumi Ueda (1,2,3,*)
(1) Mental Health Research Institute, and Departments of (2) Pharmacology
and (3) Psychiatry, Medical School, The University of Michigan, Ann Arbor,
MI 48109, U.S.A.
(*) To whom correspondence should be addressed (1).
Abstract: 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.
Keywords: Synaptic vesicle, Neurotransmitter transport, Glutamate, Presynaptic
regulation, Inhibitory protein factor