Laboratories (Woburn, MA). 3582735838). Using pharmacological, genetic, and bioinformatics methods, the current findings show that both receptor populations up-regulate many immediate early genes involved in growth and differentiation. Activation of intracellular mGluR5 also up-regulates genes involved in synaptic plasticity including activity-regulated cytoskeletal-associated protein (Arc/Arg3.1). Mechanistically, intracellular mGluR5-mediated Arc induction is dependent upon extracellular and intracellular Ca2+and ERK1/2 as well as calmodulin-dependent kinases as known chelators, inhibitors, and HOX1H a dominant 7-xylosyltaxol negative Ca2+/calmodulin-dependent protein kinase II construct block Arc increases. Moreover, intracellular mGluR5-induced Arc expression requires the serum response transcription factor (SRF) as wild type but not SRF-deficient neurons show this response. Finally, increased Arc levels due to high K+depolarization is usually significantly reduced in response to a permeable but not an impermeable mGluR5 antagonist. Taken together, these data 7-xylosyltaxol spotlight the importance of intracellular mGluR5 in the cascade of events associated with sustained synaptic transmission. == Introduction == Glutamate, the major excitatory amino acid neurotransmitter present in the central nervous system, exerts its effects by binding and activating receptors that are classified as ionotropic (ligand-gated ion channels) or metabotropic glutamate receptors (mGluRs2; G-protein coupled receptors GPCRs). One such GPCR, mGluR5, is not only a key player in many aspects of neuronal development, synaptic plasticity, and learning and memory but 7-xylosyltaxol is also implicated in various neurological disorders such as epilepsy, fragile X syndrome, neuropathic pain, and Parkinson disease (25). Observations from this laboratory have shown that a large percentage of mGluR5 is usually expressed on intracellular membranes; ligand activation of endogenous mGluR5 on isolated, striatal nuclei prospects to rapid, sustained Ca2+responses that can be blocked by receptor-specific antagonists (1,6,7). Studies using tagged molecules and impermeable agonists and antagonists show that this ligand binding domain name is within the nuclear lumen such that glutamate or other permeable agonists such as quisqualate (Quis) must cross both the plasma and nuclear membranes to activate receptors (1,68). Mechanistically, this is accomplished via the excitatory amino acid transporters or the cystine-glutamate exchanger (1,6,7). Using optical, pharmacological, and genetic techniques, we have also exhibited that nuclear mGluR5 couples to Gq/11to activate nuclear phosphatidylinositol-phospholipase C, hydrolysis of phosphoinositol 4,5-bisphosphate, and generation of nuclear inositol 1,4,5-trisphosphate (IP3) (7). Thus, nuclear mGluR5s play a dynamic role in mobilizing Ca2+in a specific, localized fashion. What are the functional effects of activating endogenous mGluR5 expressed on striatal cell membranesversusthose expressed intracellularly? Using the permeable and impermeable mGluR5 ligands, our recent data show that activation of cell surface receptors via the impermeable agonist (S)-3,5-dihydroxyphenylglycine (DHPG) induces quick, transient Ca2+responses, whereas activation of intracellular mGluR5 with the permeable agonist Quis in the presence of impermeable antagonists prospects to sustained Ca2+responses. Membrane-specialized mGluR5-mediated Ca2+responses lead to unique cellular responses as well. For instance, activation of cell surface mGluR5 results in phosphorylation of crucial signaling entities such as c-Jun N-terminal kinase, CaMK, and CREB, whereas intracellular mGluR5 activation prospects to a cascade of molecular events starting with the phosphorylation of ERK1/2 and Elk-1 followed by the enhanced expression of synaptic plasticity genes like c-fos,egr-1,Fras, andFosB. Thus activation of intracellular mGluR5 initiates a cascade of events underlying processes with hallmarks of synaptic plasticity (1). In neurons, one IEG discovered in a screen for genes rapidly induced by synaptic activation and linked to long term synaptic adaptations is usually activity-regulated cytoskeletal-associated protein, Arc/Arg3.1 (hereafter termed Arc) (9,10). Arc, a protein enriched at the post synaptic density, is usually involved in multiple forms of neuronal plasticity: long term potentiation (LTP), long term depressive disorder (LTD), and homeostatic plasticity (10). One important function attributed to Arc is usually AMPA receptor endocytosis leading to reduced AMPA currents and LTD (9,10). Arc is also involved in local actin polymerization and LTP consolidation (10) as well as regulation of Notch1 signaling in response to neural activity (11). High levels of Arc are also found in the nucleus where it appears to associate with so-called promyelocytic leukemia body (12). These subnuclear structures are primarily composed of proteins involved in gene 7-xylosyltaxol regulation and DNA repair (13). Inasmuch as studies have shown that mGluR5 activation up-regulates Arc in the hippocampus and that this up-regulation may be crucial in synaptic plasticity and in disorders such as fragile X syndrome (14,15), it is important to determine whether this is true for other regions of the brain and whether.