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The C-terminus and Third Cytoplasmic Loop Cooperatively Activate Mouse Melanopsin Phototransduction



Juan C. Valdez-Lopez, Stephen T. Petr, Matthew P. Donohue, Robin J. Bailey, Meheret Gebreeziabher, Evan G. Cameron, Julia B. Wolf, Veronika Szalai, Phyllis R. Robinson


Melanopsin, an atypical vertebrate visual pigment, mediates non-image forming light responses including circadian photoentrainment and pupillary light reflexes, and contrast detection for image formation. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells are characterized by sluggish activation and deactivation of their light responses. The molecular determinants of mouse melanopsin's deactivation have been characterized, but a detailed analysis of melanopsin's activation is lacking. We propose that an extended 3rd cytoplasmic loop is adjacent to the proximal C-terminal region of mouse melanopsin in the inactive conformation which is stabilized by ionic interaction of these two regions. This model is supported by site-directed spin labeling and electron paramagnetic resonance spectroscopy of melanopsin, the results of which suggests a high degree of steric freedom at the 3rd cytoplasmic loop, which is increased upon C-terminus truncation, supporting the idea that these two regions are close in 3-dimensional space in wild-type melanopsin. To test for a functionally critical C-terminal conformation, calcium imaging of melanopsin mutants including a proximal C-terminus truncation (at residue 365) and proline mutation of this proximal region (H377P, L380P, Y382P) delayed melanopsin's activation rate. Mutation of all potential phosphorylation sites, including a highly conserved tyrosine residue (Y382), into alanines also delayed the activation rate. We therefore propose that melanopsin's C-terminus is proximal to intracellular loop 3 and C-terminal phosphorylation permits the ionic interaction between these two regions, thus forming a stable structural conformation that is critical for initiating G- protein signaling.
Biophysical Journal


G Protein-Coupled Receptor, Opsin, Visual Pigment, Phototransduction


Valdez-Lopez, J. , Petr, S. , Donohue, M. , Bailey, R. , Gebreeziabher, M. , Cameron, E. , Wolf, J. , Szalai, V. and Robinson, P. (2020), The C-terminus and Third Cytoplasmic Loop Cooperatively Activate Mouse Melanopsin Phototransduction, Biophysical Journal, [online],, (Accessed April 19, 2024)
Created July 20, 2020, Updated October 12, 2021