Abstract
Metabotropic glutamate receptors (mGluRs) were thought until recently to function mainly as stable homodimers, but recent work suggests that heteromerization is possible. Despite the growth in available compounds targeting mGluRs, little is known about the pharmacological profile of mGluR heterodimers. Here, this question was addressed for the mGluR2/4 heterodimer, examined by coexpressing both receptors in isolated sympathetic neurons from the rat superior cervical ganglion (SCG), a native neuronal system with a null mGluR background. Under conditions that favor mGluR2/4 heterodimer formation, activation of the receptor was not evident with the mGluR2-selective agonist (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV) or with the mGluR4 selective agonist l-(+)-2-amino-4-phosphonobutyric acid (l-AP4); however, full activation was apparent when both ligands were applied together, confirming that mGluR dimers require ligand binding in both subunits for full activation. Properties of allosteric modulators were also examined, including the findings that negative allosteric modulators (NAMs) have two binding sites per dimer and that positive allosteric modulators (PAMs) have only a single site per dimer. In SCG neurons, mGluR2/4 dimers were not inhibited by the mGluR2-selective NAM (Z)-1-[2-cycloheptyloxy-2-(2,6-dichlorophenyl)ethenyl]-1H-1,2,4-triazole (Ro 64-5229), supporting the two-site model. Furthermore, application of the mGluR4 selective PAMs N-(4-chloro-3-methoxyphenyl)-2-pyridinecarboxamide (VU0361737) or N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) and combined application of mGluR4 PAMs with the mGluR2 selective PAM biphenyl indanone-A failed to potentiate glutamate responses through mGluR2/4, suggesting that mGluR2/4 heterodimers are not modulatable by PAMs that are currently available.
Footnotes
This work was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant GM101023].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- mGluRs
- metabotropic glutamate receptors
- SCG
- superior cervical ganglion
- NAM
- negative allosteric modulator
- PAM
- positive allosteric modulator
- VU0361737 (VU036)
- N-(4-chloro-3-methoxyphenyl)-2-pyridinecarboxamide
- BINA
- biphenyl indanone-A
- PHCCC
- N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide
- l-AP4
- l-(+)-2-amino-4-phosphonobutyric acid
- DCG-IV
- (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine
- Ro 64-5229
- (Z)-1-[2-cycloheptyloxy-2-(2,6-dichlorophenyl)ethenyl]-1H-1,2,4-triazole
- PTX
- pertussis toxin.
- Received February 25, 2012.
- Accepted May 31, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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