The Study Of Activation Mechanism Of MGluR Heterodimer

G protein-coupled receptors(GPCRs)react to numerous extracellular chemical and physical signals,and recruit distinct signaling partners to deliver various cellular functions,thus show great interest of therapeutic drug targets,account for ~27% of the global market share.Whereas most GPCRs can signal as a monomer,increasing studies revealed that they can form homo/hetero dimer,until now their role in signaling remains elusive.GPCR superfamily comprises more than 800 seven-transmembrane(7TM)receptors that can be divided into four classes according to their sequence homology: Class A,Class B,Class C and Class F.Metabotropic glutamate receptors(mGluR)belong to Class C family and are divided into three groups: group I(mGluR1,5),II(mGluR2,3)and III(mGluR4,6,7,8),on the basis of sequence homology,pharmacological profile and cellular signaling.mGluR can initiate signaling by binding a very important neurotrasmitter glutamate,which perform a variety of functions in nervous systems.For example,they are involved in learning,memory,anxiety and the perception of pain.mGluRs are well-recognized strict constitutive dimers,whose dimerization is necessary for receptors' activation and have been reported to form not only homodimers but also heterodimers by combination of different subunits.However the activation mechanism of the heterodimer is unclear.We have explored the distinct activation mechanism between homodimer and heterodimer of the GPCRs by choosing mGluRs as prototypical GPCRs.We used rat metabotropic glutamate(mGlu)receptors as prototypical dimers to study the functional interaction between each subunit.mGluRs can form both constitutive homo-and heterodimers.Whereas both mGluR2 and mGluR4 couple to G proteins,G protein activation is mediated by mGluR4 heptahelical domain(HD)exclusively in mGluR2-4 heterodimers.Such asymmetric transduction results from the action of both the dimeric extracellular domain,and an allosteric activation by the partially-activated non-functional mGluR2 HD.G proteins activation by mGluR2 HD occurs if either the mGluR2 HD is occupied by a positive allosteric modulator or if mGluR4 HD is inhibited by a negative modulator.These data revealed an oriented asymmetry in mGlu heterodimers that can be controlled with allosteric modulators.They provide new insight on the allosteric interaction between subunits in a GPCR dimer.In summary,our study has showed that homodimer and heterodimer of the GPCRs are different functional entities.Although maybe they are formed by similar subunit,they showed unique properties.Just as teenagers may resemble their parents and share their genetic makeup,they can still act in a manner that is entirely unique! We believe in the importance of investigating each GPCR entity as an individual signaling complex,as they appear to act differently from each monomer constituting them.These GPCR entities must be thought as new therapeutic targets for drug screening.