Protein Kinase C and A₃Adenosine Receptor Activation Inhibit Presynaptic Metabotropic Glutamate Receptor (mGluR) Function and Uncouple mGluRs from GTP-Binding Proteins

Abstract

One of the most prominent roles of metabotropic glutamate receptors (mGluRs) in the CNS is to serve as presynaptic receptors that inhibit transmission at glutamatergic synapses. Previous reports suggest that the presynaptic effect of group II mGluRs at corticostriatal synapses can be inhibited by activators of protein kinase C (PKC). We now report that activation of PKC inhibits the ability of group II and group III mGluRs to regulate transmission at three major synapses in the hippocampal formation. Thus, this effect may be a widespread phenomenon that occurs at glutamatergic synapses throughout the CNS. We also report that this response is not limited to PKC-activating phorbol esters but that activation of A3 adenosine receptors induces a PKC-dependent inhibition of group III mGluR function at the Schaffer collateral-CA1 synapse. In addition to inhibiting mGluR modulation of excitatory synaptic transmission, we found that activation of PKC reduces inhibition of forskolin-stimulated cAMP accumulation by group II and group III mGluRs, suggesting that the effect of PKC on mGluR signaling is not specific to their effects on neurotransmitter release. This led us to test the hypothesis that PKC acts upstream from effector proteins regulated by mGluRs and acts at the level of the receptor or GTP-binding protein. Interestingly, we found that PKC inhibited mGluR-induced increases in [35S]-GTPgammaS binding in cortical synaptosomes. These data suggest that PKC-induced inhibition of mGluR signaling may be mediated by the inhibition of coupling of mGluRs to GTP-binding proteins.

Spermidine-induced improvement of reconsolidation of memory involves calcium-dependent protein kinase in rats

“…The PKC family of Ser/Thr kinases (Nishizuka 1995) regulates neuronal activity at different levels, including neurotransmitter release, neurotransmitter receptor function, and gene expression (Ben-Ari et al 1992;Meberg et al 1993;Macek et al 1998;Manseau et al 1998;Kleschevnikov and Routtenberg 2001). There are at least 10 genes coding for PKC family members.…”

CXCL16 Orchestrates Adenosine A3Receptor and MCP-1/CCL2 Activity to Protect Neurons from Excitotoxic Cell Death in the CNS

“…In contrast, in the present work we found that CXCL16 exerts neuroprotection against Glu insult only in the presence of functional A 3 R, the inactivation of all of the other ARs being unable to limit the CXCL16 effect. In rodents, among ARs, A 3 R has the lower affinity for ADO and is expressed at low levels in the brain (Ji et al, 1994), including the hippocampus (Dunwiddie et al, 1997;Macek et al, 1998) and the cerebral cortex (Brand et al, 2001). The ability of A 3 R to contribute to neuroprotection is controversial: in vivo studies suggest that differences in timing of intraperitoneal A 3 R agonist administration may alter the outcome of ischemic brain injury (Von Lubitz et al, 1995, 2001.…”

Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

“…NMDA receptors are essential to AD initiation and propagation [26]. Block of A 3 receptors, in removing A 3 receptor-mediated impairment of the feedback inhibition of glutamate release exerted by specific metabotropic glutamate receptor subtypes [42], may reduce the participation of glutamate in triggering the AD.…”