Functional metabotropic glutamate receptors on nuclei from brain and primary cultured striatal neurons: Role of transporters in delivering ligand

Yuh Jiin I. Jong, Vikas Kumar, Ann E. Kingston, Carmelo Romano, Karen L. O'Malley

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

G-protein-coupled receptors are well known for converting an extracellular signal into an intracellular response. Here we showed that the metabotropic glutamate receptor 5 (mGlu5) plays a dynamic intracellular role in signal transduction. Activation of endogenously expressed mGlu5 on striatal nuclear membranes leads to rapid, sustained calcium (Ca2+) responses within the nucleoplasm that can be blocked by receptor-specific antagonists. Extracellular ligands such as glutamate and qui squalate reach nuclear receptors viaboth sodium-dependent transporters and cystine glutamate exchangers. Inhibition of either transport system blocks radio-labeled agonist uptake as well as agonist-induced nuclear Ca2+ changes. Impermeable antagonists like LY393053 and LY367366 not only blocked [3H]quisqualate binding but also prevented nontransported agonists such as (RS)-3,5- dihydroxyphenylglycine from inducing intracellular Ca2+ changes in heterologous cells. In contrast, neither LY compound prevented quisqualate or glutamate from activating intracellular receptors leading to Ca2+ responses. Inasmuch as Ca2+ can enter the nucleoplasm via the nuclear pore complex or from the nuclear lumen, the presence of nuclear mGlu5 receptors appeared to amplify the latter process generating a faster nuclear response in heterologous cells. In isolated striatal nuclei, nuclear receptor activation results in the de novo appearance of phosphorylated CREB protein. Thus, activation of nuclear mGlu5 receptors initiates a signaling cascade that is known to alter gene transcription and regulate many paradigms of synaptic plasticity. These studies demonstrated that mGlu5 receptors play a dynamic role in signaling both on and off the plasma membrane.

Original languageEnglish
Pages (from-to)30469-30480
Number of pages12
JournalJournal of Biological Chemistry
Volume280
Issue number34
DOIs
StatePublished - Aug 26 2005

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