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M501775200v1
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Papers In Press, published online ahead of print June 15, 2005
J. Biol. Chem, 10.1074/jbc.M501775200
Submitted on February 16, 2005
Revised on June 8, 2005
Accepted on June 15, 2005

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, and Karen L. O'Malley

Anatomy and Neurobiology, Washington University School of Medicine, Saint Louis, MO 63110

Corresponding Author: omalleyk{at}pcg.wustl.edu

G-protein coupled receptors are well known for converting an extracellular signal into an intracellular response. Here, we show that the mGlu5 metabotropic glutamate receptor 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 quisqualate reach nuclear receptors via both sodium-dependent transporters and xCT exchangers. Inhibition of either transport system blocks radiolabeled 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 non-transported agonists such as DHPG 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 cAMP response element binding (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 demonstrate that mGlu5 receptors play a dynamic role in signaling both on and off the plasma membrane.


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