Metabotropic glutamate receptors and Neuronal Injury

Note: Modified diagram from Kandal et al., Principles of Neural Science (Elsevier, New York, 1991)

Both neuronal networks as well as neuronal transmitters have been shown to modulate neuronal plasticity and neuronal survival. More recently, the nine cloned metabotropic receptor subtypes (mGluR1a, mGluR1ß, mGluR1c, mGluR2, mGluR3, mGluR4, mGluR5, mGluR6, and mGluR7) have been linked to the modulation of neuronal survival. They function through several signal transduction pathways such as cAMP, protein kinase C (PKC), inositol phosphate, ion channel flux, and phospholipase D. Activation of the metabotropic receptors can reduce N-methyl-D-aspartate (NMDA) toxicity in retinal cells and in cortical neurons, lessen epileptiform activity in the rat cortex, protect synaptic transmission during periods of hypoxia, and increase neuronal survival during nitric oxide (NO) exposure.

The mechanisms that mediate neuroprotection by this group of receptors during ischemic disease are not clear. During cerebral ischemia, glutamate receptor activation can lead to both calcium influx into neurons and the production of NO. Nitric oxide synthase (NOS) is known to be induced in hippocampal astrocytes during this period with the subsequent generation of NO in the cerebral cortex. In addition, glutamate receptors have been reported to directly stimulate NO production in neurons. Inhibition of NO production in vitro during glutamate toxicity or during anoxia is protective against neuronal cell death. Thus, changes in metabotropic glutamate receptor activity, such as in the hippocampus, may represent one of the pathways that influences anoxic neuronal cell death and NO toxicity during cerebral ischemia.

Neuroprotection via the metabotropic glutamate receptors also may be mediated through specific signal transduction pathways. Metabotropic glutamate receptor function may require the activation of second messengers such as PKC. PKC also can function as a feedback mechanism on metabotropic glutamate activity and can reduce the inhibitory effects of this receptor on excitatory transmission at corticostriatal synapses. PKC activation independently has been linked to ischemic neurodegeneration. Antagonism of PKC activity has been shown to reduce neuronal death during toxicity associated with glutamate, kainate, anoxia, and NO.

Modulation of protein kinase A (PKA) activity may mediate the neuroprotective ability of metabotropic receptor activation during ischemia. Some metabotropic glutamate receptor subtypes, such as those responsive to 1S,3R-ACPD, have been shown to increase cAMP levels. Activation of PKA can be neuroprotective. For example, pharmacological activators of PKA, like PDGF, can protect fibroblasts from the toxic effects of serum deprivation and increased PKA activity increases neuronal survival during NO toxicity.

Thus, we are examining whether metabotropic glutamate receptor activity modulates neuronal survival during anoxia and NO toxicity, and whether this modulation is dependent upon the PKC and PKA pathways. We have recently demonstrated that activation of metabotropic glutamate receptors protects hippocampal neurons from anoxia and NO toxicity and that the mechanism of protection by these receptors may involve modulation of both PKC and PKA.