Selective actions of novel allosteric modulators reveal functional heteromers of metabotropic glutamate receptors in the CNS

• Published in: The Journal of neuroscience 2014-01, Vol.34 (1), p.79-94
• Main Authors: Yin, Shen, Noetzel, Meredith J, Johnson, Kari A, Zamorano, Rocio, Jalan-Sakrikar, Nidhi, Gregory, Karen J, Conn, P Jeffrey, Niswender, Colleen M
• Format: Article
• Language: English
• Subjects: Allosteric Regulation - drug effects; Allosteric Regulation - physiology; Animals; Brain - drug effects; Brain - physiology; Cells, Cultured; Central Nervous System - drug effects; Central Nervous System - physiology; Excitatory Amino Acid Agonists - chemistry; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - pharmacology; Female; HEK293 Cells; Humans; Male; Mice; Mice, Inbred ICR; Protein Multimerization; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - chemistry; Receptors, Metabotropic Glutamate - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1129-13.2014

Metabotropic glutamate (mGlu) receptors play important roles in regulating CNS function and are known to function as obligatory dimers. Although recent studies have suggested heterodimeric assembly of mGlu receptors in vitro, the demonstration that distinct mGlu receptor proteins can form heterodimers or hetero-complexes with other mGlu subunits in native tissues, such as neurons, has not been shown. Using biochemical and pharmacological approaches, we demonstrate here that mGlu2 and mGlu4 form a hetero-complex in native rat and mouse tissues which exhibits a distinct pharmacological profile. These data greatly extend our current understanding of mGlu receptor interaction and function and provide compelling evidence that mGlu receptors can function as heteromers in intact brain circuits.