Positive feedback of glutamate exocytosis by metabotropic presynaptic receptor stimulation

Abstract

Glutamate is important in several forms of synaptic plasticity such as long-term potentiation, and in neuronal cell degeneration. Glutamate activates several types of receptors, including a metabotropic receptor that is sensitive to trans-1-amino-cyclopenthyl-1,3-dicarboxylate, coupled to G protein(s) and linked to inositol phospholipid metabolism. The activation of the metabotropic receptor in neurons generates inositol 1,4,5-trisphosphate, which causes the release of Ca2+ from intracellular stores and diacylglycerol, which activates protein kinase C. In nerve terminals, the activation of presynaptic protein kinase C with phorbol esters enhances glutamate release. But the presynaptic receptor involved in this protein kinase C-mediated increase in the release of glutamate has not yet been identified. Here we demonstrate the presence of a presynaptic glutamate receptor of the metabotropic type that mediates an enhancement of glutamate exocytosis in cerebrocortical nerve terminals. Interestingly, this potentiation of glutamate release is observed only in the presence of arachidonic acid, which may reflect that this positive feedback control of glutamate exocytosis operates in concert with other pre- or post-synaptic events of the glutamatergic neurotransmission that generate arachidonic acid. This presynaptic glutamate receptor may have a physiological role in the maintenance of long-term potentiation where there is an increase in glutamate release mediated by postsynaptically generated arachidonic acid.

Neurotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells

“…Although the physiological roles of Ca 2+ -independent forms have not been fully clarified, it is known that PKC-ε is most abundant in the brain and present mainly in the presynaptic component (Saito et al, 1993). This form has been suggested to be a candidate isozyme associated with this presynaptic mechanism of LTP (Herreo et al, 1992). Since PKC-ε has been associated with a variety of pivotal biological events in neuronal cells, it is feasible that altered subcellular distribution of this particular isozyme may play important roles in the TCDD-induced neurotoxicity.…”

Presynaptic plasticity: The regulation of Ca2+-dependent transmitter release

“…Alternatively, the other branch of phospholipase C activation, through diacylglycerol and its activation of protein kinase C is even more important in nerve terminals. Recent data from the laboratory of Sanchez-Prieto (Herrero et al, 1992) suggest that the potentiating effect of metabotrope glutamate receptors during high frequency stimulation may arise from a synergy between diacyiglycerol-induced activation of protein kinase C and arachidonic acid, which may be released from postsynaptic cells during high-frequency stimulation (see below). This is in line with an older observation that presynaptic G proteins are involved in LTP (Goh and Pennefather, 1989).…”

“…3). The activation of PKC attenuates the presynaptic input-output relation by manipulating the repolarization through phosphorylation of K + channels and hereby prolonging Ca :+ channel opening and Ca :+ entrance (see Tibbs et al, 1989;Barrie et al, 1991;Herrero et al, 1992), by regulating the availability of Ca 2+ buffering components through phosphorylation of B-50 and MARCKS-protein (Alexander et al, 1987(Alexander et al, , 1988Graft et al, 1989;McIlroy et al, 1991;Hartwig et al, 1992), by modulating transmitter production through phosphorylation of tyrosine hydroxylase (Woodrow et al, 1992) and probably by modulating recruitment, docking or release of small synaptic vesicles through phosphoryiation of P96 (Robinson 1991, Sim et al, 1991. These mechanisms may also be involved in the maintenance of long term potentiation, since presynaptic PKCactivity was found to correlate with the induction of LTP and increased transmitter release has been implicated in the mechanisms underlying LTP (Bfir et al, 1980(Bfir et al, , 1982Tielen et al, 1983;Lovinger et al, 1985Lovinger et al, , 1986Gianotti et al, 1992).…”

“…It may rather potentiate the effect of a constant amount of presynaptically released neurotransmitter by increasing its extracellular half-life. Alternatively, arachidonic acid was also found to produce a true presynaptic modulation by a synergistic effect with presynaptic glutamate receptor activation on PKC activity, proposed to potentiate presynaptic stimulus-secretion coupling through phosphorylation of K + channels (Herrero et al, 1992). Still several questions remain unresolved.…”

The glutamatergic nerve terminal

“…Recent evidence from the laboratory of Sanchez-Prieto (Herrero et al, 1992a) has provided evidence that PKC in glutamatergic terminals may be activated by glutamate itself, via an excitatory presynaptic G-protein-coupled autoreceptor. decreasing the depolarization (E).…”