Modulation of the intracellular calcium concentration in photoreceptor terminals by a presynaptic metabotropic glutamate receptor

Fast excitatory neurotransmission in the central nervous system is mediated through glutamate acting on ionotropic glutamate receptors, However, gluta mate acting on metabotropic glutamate receptors (mGluRs) can also exert an inhibitory action. Here, we report by immunocytochemistry and physiology, t o our knowledge, the first glutamate receptor to be found in terminals of p hotoreceptors in the mammalian retina-the group III metabotropic glutamate receptor mGluR8, Glutamate is the transmitter of photoreceptors, and thus m GluR8 functions as an autoreceptor. Activation of mGluR8 by the group III m GluR agonists L-2-amino-4-phosphonobutyrate and L-serine-O-phosphate, or by glutamate itself, evokes a decrease in the intracellular calcium ion conce ntration ([Ca2+](i)) in isolated photoreceptors. This effect is blocked by the group III mGluR antagonists (RS)-alpha-methyl-4-phosphonophenylglycine and (RS)-alpha-methylserine-O-phosphate. Agonists for other classes of glut amate receptors-N-methyl-D-aspartic acid, quisqualic acid, kainic acid, or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-have no effec t on the [Ca2+](i) in isolated photoreceptors. The down-regulation of the [ Ca2+](i) in photoreceptors by mGluR8 provides evidence for an inhibitory fe edback loop at the photoreceptor synapse in the mammalian retina. This nega tive feedback may be a mechanism for the fine adjustment of the light-regul ated release of glutamate from photoreceptors and may serve as a safety dev ice against excitotoxic levels of release at this tonic synapse. Such a mec hanism may provide a model for feedback inhibition in other parts of the ce ntral nervous system.