Adenosine A1 and class II metabotropic glutamate receptors mediate shared presynaptic inhibition of retinotectal transmission

Presynaptic inhibition is one of the major control mechanisms in the CNS. P reviously we reported that adenosine Al receptors mediate presynaptic inhib ition at the retinotectal synapse of goldfish. Here we extend these finding s to metabotropic glutamate receptors (mGluRs) and report that presynaptic inhibition produced by both Al adenosine receptors and group II mGluRs is d ue to Gi protein coupling to inhibition of N-type calcium channels in the r etinal ganglion cells. Adenosine (100 mu M) and an Al (but not A2) receptor agonist reduced calcium current (ICa2+) by 16-19% in cultured retinal gang lion cells, consistent with their inhibition of retinotectal synaptic trans mission (-30% amplitude of field potentials). The general metabotropic glut amate receptor (mGluR) agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic a cid (1S,3R-ACPD, 50 mu M) and the selective group II mGluR receptor agonist (2S,2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl)glycine (DCG-IV, 300 nM) inhib ited both synaptic transmission and ICa2+ whereas the group III mGluR agoni st L-2-amino-4-phosphono-butyrate (L-AP4) inhibited neither synaptic transm ission nor ICa2+. When the N-type calcium channels were blocked with omega- conotoxin GVIA, both adenosine and DCG-IV had much smaller percentage effec ts on the residual 20% of ICa2+ suggesting effects mainly on the N-type cal cium channels. The inhibitory effects of A1 adenosine receptors and mGluRs were both blocked by pertussis toxin, indicating that they are mediated by either Gi or G(o). They were also inhibited by activation of protein kinase C (PKC), which is known to phosphorylate and inhibit G(i). Finally, when a pplied sequentially, inhibition by adenosine and DCG-IV were not additive b ut occluded each other. Together these results suggest that adenosine A1 re ceptors and group LT mGluRs mediate presynaptic inhibition of retinotectal synaptic transmission by sharing a pertussis toxin (PTX)-sensitive, PKC-reg ulated G(i) protein coupled to N-type calcium channels.