The Specific Monomer/Dimer Equilibrium of the Corticotropin-releasing Factor Receptor Type 1 Is Established in the Endoplasmic Reticulum
Journal of Biological Chemistry(2014)
Abstract
Background: GPCRs may be expressed in a monomer/dimer equilibrium at the plasma membrane. Results: For the dimeric CRF1R, we found a constant monomer/dimer equilibrium not only at the plasma membrane but also in the ER. Conclusion: The monomer/dimer equilibrium of the CRF1R is established already in the ER. Significance: Our findings shed new light on the monomer/dimer equilibrium of GPCRs and on ER functions.G protein-coupled receptors (GPCRs) represent the most important drug targets. Although the smallest functional unit of a GPCR is a monomer, it became clear in the past decades that the vast majority of the receptors form dimers. Only very recently, however, data were presented that some receptors may in fact be expressed as a mixture of monomers and dimers and that the interaction of the receptor protomers is dynamic. To date, equilibrium measurements were restricted to the plasma membrane due to experimental limitations. We have addressed the question as to where this equilibrium is established for the corticotropin-releasing factor receptor type 1. By developing a novel approach to analyze single molecule fluorescence cross-correlation spectroscopy data for intracellular membrane compartments, we show that the corticotropin-releasing factor receptor type 1 has a specific monomer/dimer equilibrium that is already established in the endoplasmic reticulum (ER). It remains constant at the plasma membrane even following receptor activation. Moreover, we demonstrate for seven additional GPCRs that they are expressed in specific but substantially different monomer/dimer ratios. Although it is well known that proteins may dimerize in the ER in principle, our data show that the ER is also able to establish the specific monomer/dimer ratios of GPCRs, which sheds new light on the functions of this compartment.
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Key words
Confocal Microscopy, Endoplasmic Reticulum (ER), Fluorescence Correlation Spectroscopy (FCS), G Protein-coupled Receptor (GPCR), Plasma Membrane, Corticotropin-releasing Factor Receptors, Fluorescence Cross-correlation Spectroscopy, Monomer, Oligomer Equilibrium, Receptor Oligomerization
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