Activation of metabotropic glutamate receptors by L-AP4 stimulates survival of rat cerebellar granule cells in culture.

The results presented here show that the metabotropic glutamate receptor agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) is capable of markedly stimulating the survival of rat cerebellar granule cells in culture. This is the first demonstration of a neurotrophic role for metabotropic glutamate receptors. The survival promoting action of L-AP4 does not involve a large, rapid rise in [Ca2+]i which is seen with other neurotrophic agents in granule cells such as N-methyl-D-aspartate, ionomycin and high potassium. In addition, the survival-promoting effect of L-AP4 did not appear to be related to changes in cAMP levels. Survival due to L-AP4 was enhanced by pertussis toxin and by forskolin and was unaffected by inhibitors of cAMP-dependent protein kinase. Measurement of cAMP levels after long-term treatment with neurotrophic agents showed no clear relationship between cAMP concentration and granule cell survival. The mechanism of L-AP4 stimulated cell survival is unknown but seems unlikely to involve an acute rise in [Ca2+]i or modulation of cAMP levels. Survival induced by L-AP4 was not blocked by the antagonist (RS)-alpha-methyl-4-carboxyphenylglycine. Similarity in these properties with those of the mGLu7 receptor suggests that granule cell survival was stimulated by an mGlu7-like metabotropic receptor.