Stimulation of postsynaptic and inhibition of presynaptic adenylyl cyclase activity by metabotropic glutamate receptor activation

To determine the subcellular distribution of cyclic AMP-coupled metabotropic glutamate receptors (mGluRs), the effects of glutamate agonists on adenylyl cyclase activity were examined using two hippocampal membrane preparations. These were synaptosomes (SY), which are composed of presynaptic terminals, and synaptoneurosomes (SN), which are composed of both pre- and postsynaptic elements. In SY, a water-soluble analogue of forskolin (7 beta-forskolin) increased enzyme activity approximately 10-fold at the highest concentration tested. The selective metabotropic receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) inhibited enzyme activity as did glutamate and quisqualate. L-Amino-4-phosphobutanoate (L-AP4) had no effect on enzyme activity at any concentration tested. The metabotropic receptor antagonist L-2-amino-3-phosphopropionic acid (L-AP3) was not effective in the SY in antagonizing the agonist-induced decreases in adenylyl cyclase activity by glutamate or 1S,3R-ACPD. It was, however, effective at antagonizing quisqualate-induced decreases in enzyme activity. In SN, at the highest concentration tested, 7 beta-forskolin produced a 60-fold increase in adenylyl cyclase activity. As was observed in SY, glutamate decreased adenylyl cyclase activity in SN. In contrast, 1S,3R-ACPD, quisqualate, and L-AP4 increased adenylyl cyclase activity. In the SN, L-AP3 was ineffective in antagonizing any agonist-induced increases (1S,3R-ACPD, L-AP4, and quisqualate) or decreases (glutamate) in adenylyl cyclase activity. The data suggest that postsynaptic metabotropic glutamate receptor activation results in stimulation of adenylyl cyclase activity, whereas inhibition of this enzyme appears to be mediated at least partly through presynaptic mechanisms.