Intracellular Ligand for Glutamate Receptors

Science's STKE  26 Jun 2001:
Vol. 2001, Issue 88, pp. tw2
DOI: 10.1126/stke.2001.88.tw2

Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors. The mGluR1a, 5a, and 5b isoforms with extended COOH-termini are constitutively active when expressed in nonneuronal cells, such as HEK293 cells. However, natively expressed mGluR1a or transfected mGluR5a expressed in cerebellar granule cells are not constitutively active. Ango et al. show that agonist-independent activation of endogenous mGluR1a can be induced in cerebellar granule cells by decreasing the expression of Homer3 using antisense RNA. Homer proteins are known to interact with mGluRs and are involved in organizing postsynaptic density structures. Expression of a mutant of mGluR5a that cannot interact with Homer also resulted in agonist-independent activity, further confirming that Homer regulates the receptor activation state. The Homer1a isoform is expressed in response to increases in neuronal activity and this protein competes with Homer3 for interaction with the mGluRs. Treatments that increase Homer1a expression resulted in agonist-independent activation of mGluR1a. Homers appear to be intracellular ligands for this subset of mGluRs and changes in the balance of neuronal Homer isoforms provides a mechanism for regulating the activity of these mGluRs in response to neuronal activity.

F. Ango, L. Prézeau, T. Muller, J. C. Tu, B. Xiao, P. F. Worley, J. P. Pin, J. Bockeart, L. Fagni, Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature 411, 962-965 (2001). [Online Journal]