Mitogen-activated protein kinases (MAPKs) are expressed in postmitotic neuronal cells of adult mammalian brain and are involved in the regulation of various cellular activities, including inducible gene expression. Recent data from this laboratory show that selective stimulation of metabotropic glutamate receptor 5 (mGluR5) activates a major subclass of MAPKs, extracellular signal-regulated protein kinase ( ERK), in striatal neurons. The activation of ERK was mediated partially through the mGluR5-associated signaling pathway, i. e., inositol-1,4,5-triphosphate (IP3 )-mediated Ca2+ release. More importantly, the member of Homer family, Homer1b/c, forms a central signaling pathway linking mGluR5 to ERK in a Ca2+ -independent manner. In addition, a major serine/threonine phosphatase, protein phosphatase 2A (PP2A), is also involved in the mGluR5 regulation of ERK phosphorylation. As an information superhighway between the surface membrane and the nucleus, ERK when co-activated by both IP3/Ca2+- and Homer1 b/c-dependent pathways showed the ability to phosphorylate two transcription factors, Elk-1 and cAMP response element-binding protein (CREB),and thereby facilitated c-Fos expression. Together, available data obtained from this laboratory and others indicate that mGluR5 possesses the ability to activate the ERK pathway in striatal neurons. A sophisticated signaling apparatus involving coordinated interactions between protein kinases and protein phosphatases mediates the mGluR5-ERK coupling imperative for the transcriptional regulation.