Akademik Veri Yönetim Sistemi
ERNEST 8th and Final Meeting GPCR Structure and Function: The present and perspectives for the future, Heraklion, Yunanistan, 3 - 07 Mayıs 2023, ss.24, (Özet Bildiri)
Orphan G
protein-coupled receptors represent a largely unexplored resource, with a therapeutic
potential for the treatment of a variety of diseases. Among these, GPR37
is of particular interest since it is extensively expressed in the brain and
central nervous system; yet its physiological function is unknown. GPR37
was shown to be related to the dopaminergic system and brain myelination.
Insoluble aggregates of GPR37, substrate of parkin, accumulate in brain tissue
samples of Parkinson’s disease patients, including Lewy bodies and neurites.
Parkin activates the clearance of unfolded GPR37, whereas the
overexpression of GPR37 in the absence of parkin can result in unfolded
protein-induced cell death. In addition, GPR37's ligand protects cells from
neurotoxicity, but its loss has the same effect. Hence, it is still debatable
whether GPR 37 is neuroprotective or neurotoxic. Since autophagy contributes to
the clearance of damaged organelles and misfolded proteins within neurons, we
are primarily interested in determining the relationship between GPR37 function
and autophagy.
It is known
that dimerization and oligomerization of GPCRs are important for the allosteric
modulation of GPCR activity and pharmacology. In this regard, advanced
quantitative imaging techniques revealed that GPR37 forms homodimers in living
N2a cells (1). However, the structural details of these interactions between
homodimers remain unclear. Consequently, we approximated the potential
structures of GPR37 homodimers and the residues implicated in this interaction
using a template-based molecular modeling approach based on available homodimer
crystal and cryo-EM structures (2-5). Our hypothesized structure of GPR37
homodimers has an interface including the transmembrane (TM) domains TM1, TM2,
and H8, as was previously found for the structures of rhodopsin, opsin,
kappa-opioid, and 1 adrenergic receptors (2-5). In the future, our GPR37
homodimer models will be refined using molecular dynamics simulations in a
lipid bilayer. The dimerization interface will allow us to design additional
experiments, including mutagenesis and peptide-interference assays, to
understand better the function of GPR37 homodimers.
Overall, we aim
to determine the function of GPR37 monomers and oligomers in Hep3B cell
signaling processes in relation to autophagy.
Acknowledgments:
This work was supported by Acibadem University Scientific Research Projects
Commission (Project No: 2020/03/11)
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