title: Pharmacological characterization of mGlu1 receptors in cerebellar granule cells reveals biased agonism.
abstract: The majority of existing research on the function of metabotropic glutamate (mGlu) receptor 1 focuses on G protein-mediated outcomes. However, similar to other G protein-coupled receptors (GPCR), it is becoming apparent that mGlu1 receptor signaling is multi-dimensional and does not always involve G protein activation. Previously, in transfected CHO cells, we showed that mGlu1 receptors activate a G protein-independent, β-arrestin-dependent signal transduction mechanism and that some mGlu1 receptor ligands were incapable of stimulating this response. Here we set out to investigate the physiological relevance of these findings in a native system using primary cultures of cerebellar granule cells. We tested the ability of a panel of compounds to stimulate two mGlu1 receptor-mediated outcomes: (1) protection from decreased cell viability after withdrawal of trophic support and (2) G protein-mediated phosphoinositide (PI) hydrolysis. We report that the commonly used mGlu1 receptor ligands quisqualate, DHPG, and ACPD are completely biased towards PI hydrolysis and do not induce mGlu1 receptor-stimulated neuroprotection. On the other hand, endogenous compounds including glutamate, aspartate, cysteic acid, cysteine sulfinic acid, and homocysteic acid stimulate both responses. These results show that some commonly used mGlu1 receptor ligands are biased agonists, stimulating only a fraction of mGlu1 receptor-mediated responses in neurons. This emphasizes the importance of utilizing multiple agonists and assays when studying GPCR function.
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, D.C. 20057, USA. Electronic address: hah32@georgetown.edu.
authors.forename: Hannah A
authors.initials: HA
authors.lastname: Hathaway
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, D.C. 20057, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Pshenichkin
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, D.C. 20057, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Grajkowska
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, D.C. 20057, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Gelb
authors.affiliation: Section on Molecular Neuroscience, National Institute of Mental Health IRP, Bldg 49, Room 5A27, Bethesda, MD 20892, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Emery
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, D.C. 20057, USA.
authors.forename: Barry B
authors.initials: BB
authors.lastname: Wolfe
authors.affiliation: Department of Pharmacology and Physiology, Georgetown University, Washington, D.C. 20057, USA.
authors.forename: Jarda T
authors.initials: JT
authors.lastname: Wroblewski
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019390:Arrestins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006868:Hydrolysis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D018683:Excitatory Amino Acid Agents; D010716:Phosphatidylinositols; D018094:Receptors, Metabotropic Glutamate; D000071557:beta-Arrestins; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D011188:Potassium
keywords: Biased agonism; Cerebellar granule cells; DHPG; Glutamate; Metabotropic glutamate receptor 1; Quisqualate