A Decrease in [Ca²⁺]_c but not in cAMP Mediates L‐AP4 Inhibition of Glutamate Release: PKC‐mediated Suppression of this Inhibitory Pathway

Abstract

We investigated the mechanism of the inhibition of glutamate release by (L)-2-amino-4-phosphonobutyrate ((L)-AP4) in cerebrocortical nerve terminals from young rats (3 weeks of age). The Ca(2+)-dependent release of glutamate was reduced by (L)-AP4 in a concentration-dependent manner. This inhibitory effect was prevented by pertussis toxin, insensitive to staurosporine and associated with a reduction both in the depolarization-evoked increase in the cytoplasmic free Ca(2+) concentration ([Ca(2+)](c)) and in forskolin-stimulated cAMP formation. However, the reduction in [Ca(2+)](c) but not in cAMP seemed to be responsible for the decrease in release, since inhibition by (L)-AP4 can also be observed in the absence of detectable changes in cAMP The inhibitory modulation by (L)-AP4 was suppressed by the activation of protein kinase C with phorbol esters. The nerve terminals from young rats also exhibited a facilitatory pathway of glutamate release which was mediated by protein kinase C. Interestingly, stimulation of this pathway with the glutamate agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate in the presence of arachidonic acid also abolished the inhibitory action of (L)-AP4. The dominance of the facilitatory pathway in its interaction with the (L)-AP4-mediated inhibitory control may provide some clues to understand the presynaptic changes during synaptic plasticity.

Developmental expression of the group III metabotropic glutamate receptor mGluR4a in the medial nucleus of the trapezoid body of the rat

“…It has been established in several synaptic systems that L-AP4 exerts an inhibition of excitatory neurotransmission by reducing the release of neurotransmitter as a result of the activation of presynaptic metabotropic glutamate receptors (Schoepp and Conn, 1993;Herrero et al, 1996;Pekhletski et al, 1996). These observations have been further supported by a presynaptic immunolocalization of mGluR4, mGluR7, and mGluR8 in pathways exhibiting a presynaptic modulation by L-AP4-sensitive receptors (Kinoshita et al, 1996a,b;Shigemoto et al, 1996Shigemoto et al, , 1997Kinzie et al, 1997;Mateos et al, 1998).…”

Diurnal and circadian variation of protein kinase C immunoreactivity in the rat retina

“…On the other hand, L-AP4, which activates group III glutamate metabotropic receptors, usually is associated with inhibition of calcium currents and transmitter release (Trombley and Westbrook, 1992), actions that are independent of the PKC pathway but that often are opposed by PKC activated by some other means (Herrero et al, 1996).…”

The Metabotropic Glutamate Receptor mGlu7 Activates Phospholipase C, Translocates Munc-13-1 Protein, and Potentiates Glutamate Release at Cerebrocortical Nerve Terminals

“…Most group III mGlu receptors (mGlu4, -6, -7, and -8 receptors) are located within the presynaptic active zone (1) where they act as autoreceptors mediating feedback inhibition of glutamate release (2)(3)(4). The signaling mechanism initiated by mGlu7 receptors to inhibit neurotransmitter release involves the activation of G i/o proteins that inhibit Ca 2ϩ channels and adenylyl cyclase (5), and probably the release process itself (6).…”