Selective Actions of Novel Allosteric Modulators Reveal Functional Heteromers of Metabotropic Glutamate Receptors in the CNS

Abstract

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 mGlu 2 and mGlu 4 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.

Cooperative Signaling between Homodimers of Metabotropic Glutamate Receptors 1 and 5

“…Our more recent study (Kammermeier, 2012a) confirmed that the mGluR2/4 interaction is consistent with a heterodimer interaction. Furthermore, Yin et al (2014) recently identified native mGluR2/mGluR4 heterodimers in prefrontal cortical neurons. When coexpressed in SCG neurons (Kammermeier, 2012a), mGluR2 and mGluR4 formed a pharmacologically unique receptor that could not be strongly activated by specific orthosteric agonists, but was fully activated by glutamate and by combining mGluR2-and mGluR4-targeted selective agonists DCG-IV [(2S,29R,39R)-2-(29,39-dicarboxycyclopropyl)glycine] and L-AP4 [L-(1)-2-amino-4-phosphonobutyric acid], respectively.…”

“…Until recently, most mGluRs, which form stable, covalently linked dimers (Romano et al, 1996;Ray and Hauschild, 2000;Tsuji et al, 2000;Kunishima et al, 2000;Romano et al, 2001), were thought to primarily function as homodimers. Recent work has shown that some combinations of mGluRs can form heteromeric receptors (Doumazane et al, 2011), including some (e.g., mGluR2 and mGluR4) that form heterodimers in heterologous systems (Doumazane et al, 2011) and in neurons (Kammermeier, 2012a;Yin et al, 2014).…”

Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

“…Another important consideration in assessing allosteric modulator pharmacology in native systems is the fact that the mGlu family are obligate dimers (El-Moustaine et al, 2012) that also have the capacity to form heteromers with other subtypes (Doumazane et al, 2011;Kammermeier, 2012;Sevastyanova and Kammermeier, 2014;Yin et al, 2014) as well as with other unrelated GPCRs (Gama et al, 2001;Gonzalez-Maeso et al, 2008;Cabello et al, 2009). Unsurprisingly, such complexity in receptor configurations can influence the pharmacology of small molecules.…”

“…Unsurprisingly, such complexity in receptor configurations can influence the pharmacology of small molecules. Heterodimerization of mGlu 4 and mGlu 2 has differential effects on the pharmacology of different allosteric ligands (Kammermeier, 2012;Yin et al, 2014 (Yin et al, 2014). This perturbation in the pharmacology of allosteric ligands has consequences in vivo at synapses where mGlu 2 and mGlu 4 are coexpressed.…”

“…VU0155041 and Lu AF21934 are both effective at potentiating the actions of L-AP4 at corticostriatal synapses (Gubellini et al, 2001;Yin et al, 2014). However, PHCCC does not potentiate the actions of L-AP4 at corticostriatal synapses (Yin et al, 2014), despite being an efficacious mGlu 4 PAM of L-AP4-induced responses at other synapses (Marino et al, 2003;Valenti et al, 2005;Jones et al, 2008). Direct protein-protein interactions are not necessarily required for a coexpressed receptor to impact the pharmacological effect of an mGlu ligand.…”