Research Article
The mGluR6 ligand-binding domain, but not the C-terminal domain, is required for synaptic localization in retinal ON-bipolar cells

https://doi.org/10.1016/j.jbc.2021.101418Get rights and content
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Signals from retinal photoreceptors are processed in two parallel channels—the ON channel responds to light increments, while the OFF channel responds to light decrements. The ON pathway is mediated by ON type bipolar cells (BCs), which receive glutamatergic synaptic input from photoreceptors via a G-protein-coupled receptor signaling cascade. The metabotropic glutamate receptor mGluR6 is located at the dendritic tips of all ON-BCs and is required for synaptic transmission. Thus, it is critically important for delivery of information from photoreceptors into the ON pathway. In addition to detecting glutamate, mGluR6 participates in interactions with other postsynaptic proteins, as well as trans-synaptic interactions with presynaptic ELFN proteins. Mechanisms of mGluR6 synaptic targeting and functional interaction with other synaptic proteins are unknown. Here, we show that multiple regions in the mGluR6 ligand-binding domain are necessary for both synaptic localization in BCs and ELFN1 binding in vitro. However, these regions were not required for plasma membrane localization in heterologous cells, indicating that secretory trafficking and synaptic localization are controlled by different mechanisms. In contrast, the mGluR6 C-terminus was dispensable for synaptic localization. In mGluR6 null mice, localization of the postsynaptic channel protein TRPM1 was compromised. Introducing WT mGluR6 rescued TRPM1 localization, while a C-terminal deletion mutant had significantly reduced rescue ability. We propose a model in which trans-synaptic ELFN1 binding is necessary for mGluR6 postsynaptic localization, whereas the C-terminus has a role in mediating TRPM1 trafficking. These findings reveal different sequence determinants of the multifunctional roles of mGluR6 in ON-BCs.

Keywords

retina
synapse
metabotropic glutamate receptor (mGluR)
photoreceptor
trafficking

Abbreviations

BC
bipolar cell
CSNB
congenital stationary night blindness
CT
C-terminal tail
LBD
ligand-binding domain
OPL
outer plexiform layer
TRPM1
transient receptor potential melastatin

Cited by (0)

Present address for Melina A. Agosto: Retina and Optic Nerve Research Laboratory, Department of Physiology and Biophysics, and Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada.

Present address for Nitin Kumar: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.