Activation of Intracellular Metabotropic Glutamate Receptor 5 in Striatal Neurons Leads to Up-regulation of Genes Associated with Sustained Synaptic Transmission Including Arc/Arg3.1 Protein

Abstract

Background: Many GPCRs including mGluR5 are expressed on cell surface and intracellular membranes although their intracellular functions are unknown. Results: Activation of intracellular mGluR5 in neurons up-regulates many genes associated with synaptic plasticity like Arc. Conclusion: Intracellular mGluR5 is critical for synaptic plasticity. Significance: Learning how intracellular mGluR5 signals is crucial for understanding neurodevelopmental disorders with disrupted synaptic plasticity like fragile X and autism.

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

“…Similarly, dynorphin B, an agonist of the κ opioid receptor, increases opioid peptide transcription in isolated cardiac nuclei [19]. In nuclei isolated from non-cardiac cells, Ang II [20], bradykinin B2 [21], prostaglandin E 2 [22][23][24], lysophosphatidic acid type-1 [25,26], metabotropic glutamate type-5 [27,28], thromboxane A2 [29,30], and urotensin-II [31] receptor activation also altered gene expression. Hence, endothelin receptors couple to effectors within the nuclear membrane and may be involved in stimulus-transcription coupling.…”

Location-Dependent Signaling of the Group 1 Metabotropic Glutamate Receptor mGlu5

“…Recent, elegant evidence using conformation-specific single-domain antibodies to directly assess activation of the b 2 -adrenergic receptor confirmed bona fide GPCR signaling from early endosomes (Irannejad et al, 2013). Additional evidence comes from strategies using pharmacological isolation of endogenous intracellular mGlu5 receptors on either the ER or nuclear membrane of primary hippocampal or striatal neurons (Jong et al, 2009;Kumar et al, 2012;Purgert et al, 2014). Interestingly, a mutant version of the V 2 vasopressin receptor, which cannot be trafficked to the plasma membrane and instead localizes within intracellular compartments, responded to agonists, suggesting that intracellular receptors can be functional even when mistrafficked (Robben et al, 2009).…”

“…Downstream targets of Elk-1 activation, such as Erg1 and cFos, were also activated by intracellular mGlu5 receptors as were Fos, Fos related antigen, Fosl1, Fosl2, and Fosb (Jong et al, 2009 Pharmacological isolation also allows the use of unbiased bioinformatics approaches to determine what other genes might be affected by plasma membrane or intracellular receptor activation. This approach showed that many of the transcripts upregulated by quisqualate alone were transcription factors involved in neuronal survival and growth (activating transcription factor 3, nuclear receptor subfamily 4 group A member 1, Tribbles homolog 1, cAMP responsive element modulator, JunB, and AT-rich interactive domaincontaining protein 5A) as well as effector proteins, such as activity-regulated cytoskeletal-associated protein (Arc), which is involved in gene regulation and synaptic plasticity (Kumar et al, 2012). Because Arc is critical for long-term memory and synaptic plasticity, these studies suggest that intracellular mGlu5 receptors play a major role in the transcriptional regulation of genes associated with sustained synaptic transmission (Kumar et al, 2012).…”

“…This approach showed that many of the transcripts upregulated by quisqualate alone were transcription factors involved in neuronal survival and growth (activating transcription factor 3, nuclear receptor subfamily 4 group A member 1, Tribbles homolog 1, cAMP responsive element modulator, JunB, and AT-rich interactive domaincontaining protein 5A) as well as effector proteins, such as activity-regulated cytoskeletal-associated protein (Arc), which is involved in gene regulation and synaptic plasticity (Kumar et al, 2012). Because Arc is critical for long-term memory and synaptic plasticity, these studies suggest that intracellular mGlu5 receptors play a major role in the transcriptional regulation of genes associated with sustained synaptic transmission (Kumar et al, 2012). Taken together, at least in striatal neurons, intracellular mGlu5 receptors can activate different pathways than mGlu5 receptors on the cell surface.…”

“…Thus, for any of these compounds to get into the cell, there must be an active transport/exchange process like the sodium or chloridedependent processes described above (Jong et al, 2005(Jong et al, , 2009Kumar et al, 2008). Besides impermeable, nontransported agonists, impermeable, nontransported antagonists exist, such as the Lilly compound, LY393053 [(6)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl)propionic acid] (Kingston et al, 2002), which can block cell surface-mediated mGlu5 receptor responses (Jong et al, 2005(Jong et al, , 2009Kumar et al, 2008Kumar et al, , 2012Purgert et al, 2014). By contrast, LY393053 did not block uptake of quisqualate or glutamate into the cells and thus did not block the functional Ca 21 responses generated by the intracellular mGlu5 receptor (Jong et al, 2005;Purgert et al, 2014).…”