Research On The Monomer Selection Mechanism In The Activation Process Of MGluR2Homodimers

Metabotropic glutamate receptors (mGluRs) belong to the Class C G-protein coupledreceptors (GPCRs), which are constitutive dimer as the same as other members of theClass C. Different form GABABR and TIR, mGluRs are constitutive homodimer, and eachmonomer consists of Venus Flytrap Modual(VFT), Cystein rich Region(CRD),Heptahelical Domain(HD) and intracellular C-terminal. The research on cis-activation ortrans-activation in homodimer activation and its activation mechanism are always hottopics. mGluRs are considered as model receptors in these researches for their stabledimerization and mutli-functional domains.We used mGluR2as the study object, and detected cis-activation or trans-activationin the activation process of homodimer and domain participating in monomer selectionmechanism. Firstly, we constructed artificial heterodimer of mGluR2and functionalmissing mutants in VFT and i3loop through molecular biology methods. Transfected theseplasmids into HEK293cells through electroporation. Flex and IP3function detectionresults showed that only trans-activation can be detected in mGluR2, different from bothcis-activation and trans-activation exsiting in mGluR5. These indicated that there must bemonomer selection mechanism in mGluR2activation. Based on differences in mGluR5and mGluR2activation mechnism, we investigated CRD fuction in the monomer selectionmechanism. The results showed that cis-activation can be detected in mGluR2afterreplacing mGluR5-CRD into mGluR2-CRD, which needs futher confirmed.In summary, this research suggested that mGluR2has only trans-activation andprobably CRD affects on the choice of particular monomer in process of activation. Theselay a foundation for research on the transduction of activation signal form VFTs-CRDs toHDs in mGluRs, even for the whole Class C GPCRs mechanism, meanwhile contributingto drug design and development targeted for the receptors.