Cholesterol dependence on the conformational changes of metabotropic glutamate receptor 1 (mGLuR1).

Abstract

Metabotropic glutamate receptors (mGluRs) are class C G-protein-coupled receptors (GPCRs) which exist as constitutive dimers. They play significant roles in regulating neurotransmission and activating excitatory synapses in the central nervous system. Besides the common GPCR-defining hepta-transmembrane domains (TMDs), the class C GPCRs specifically possess large amino-terminal extracellular domains (ECDs), which comprise an orthosteric binding region, a so-called Venus flytrap domain (VFT), and a cysteine-rich domain (CRD). The domains of mGluR1, specifically the 7TM domain has been shown to be regulated by its surrounding lipid environment, especially by cholesterol although the mechanism of regulation remains elusive. We have used all-atom molecular dynamics simulation to show the interaction of cholesterol on the local structural dynamics of mGluR1 7TM domain in an inactive model. Our simulation characterizes the conformational changes of mGluR1 in 0%, 10% and 25% cholesterol concentrated lipids. Our results reveal that cholesterol influences the conformational changes of the internal protein and acts less significantly on individual protomers. We also observe that cholesterol affects the dynamics of mGluR1 essentially in TM1 and TM2 which make up the inter-phase of the protein. Further analysis shows that low cholesterol (10% cholesterol: 90% POPC) induces more significant conformational changes in mGluR1, while the system with higher cholesterol (25% cholesterol: 75% POPC) tends to behave similarly to systems without cholesterol (0% cholesterol: 100% POPC. We also determine few significant electrostatic interactions which are formed only in 10% cholesterol but absent in the other systems which further confirms our result. Due to high sequence conservation of the TMDs of mGluRs, the molecular interactions we have observed showing cholesterol dependence in mGluR1 are likely to be applicable for other members of the mGluR family.