The protective signaling of metabotropic glutamate receptor 1 Is mediated by sustained, beta-arrestin-1-dependent ERK phosphorylation.
Metabotropic glutamate receptor 1 (mGlu1) is a G protein-coupled receptor that enhances the hydrolysis of membrane phosphoinositides. In addition to its role in synaptic transmission and plasticity, mGlu1 has been shown to be involved in neuroprotection and neurodegeneration. In this capacity, we have reported previously that in neuronal cells, mGlu1a exhibits the properties of a dependence receptor, inducing apoptosis in the absence of glutamate, while promoting neuronal survival in its presence (Pshenichkin, S., Dolińska, M., Klauzińska, M., Luchenko, V., Grajkowska, E., and Wroblewski, J. T. (2008) Neuropharmacology 55, 500-508). Here, using CHO cells expressing mGlu1a receptors, we show that the protective effect of glutamate does not rely on the classical mGlu1 signal transduction. Instead, mGlu1a protective signaling is mediated by a novel, G protein-independent, pathway which involves the activation of the MAPK pathway and a sustained phosphorylation of ERK, which is distinct from the G protein-mediated transient ERK phosphorylation. Moreover, the sustained phosphorylation of ERK and protective signaling through mGlu1a receptors require expression of beta-arrestin-1, suggesting a possible role for receptor internalization in this process. Our data reveal the existence of a novel, noncanonical signaling pathway associated with mGlu1a receptors, which mediates glutamate-induced protective signaling.
Emery
Andrew C
AC
Department of Pharmacology, Georgetown University, Washington, DC 20057, USA.
Pshenichkin
Sergey
S
Takoudjou
Guy Rodrigue
GR
Grajkowska
Ewa
E
Wolfe
Barry B
BB
Wroblewski
Jarda T
JT
D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018698:Glutamic Acid; D006801:Humans; D010766:Phosphorylation; D020011:Protective Agents; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; C000605256:Arrb1 protein, rat; D019390:Arrestins; D020011:Protective Agents; D018094:Receptors, Metabotropic Glutamate; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D048049:Extracellular Signal-Regulated MAP Kinases