Melanopsin Phototransduction Is Repurposed by ipRGC Subtypes to Shape the Function of Distinct Visual Circuits

Sonoda, Takuma; Lee, Seul Ki; Birnbaumer, Lutz; Schmidt, Tiffany M.

doi:10.1016/j.neuron.2018.06.032

Cited by 95 publications

(176 citation statements)

References 70 publications

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“…Specifically, electrophysiological data in mutant mice lacking Gαq signal transduction in ipRGCs suggest the presence of an additional, cyclic nucleotide-mediated signaling cascade primarily in M4 cells, and also in M2 cells [36]. Also, melanopsin Gαq-type phototransduction is modified in M4 cells to adjust the cell's excitability for contrast sensitivity across dim and bright light [37]. Additionally, the M1 subtype is not a homogenous cell population in its biophysical properties or transcription factors [38]-instead, cells within this subtype will vary in response to light intensity [39,40].…”

Section: Plos Onementioning

confidence: 99%

Melanopsin Carboxy-terminus phosphorylation plasticity and bulk negative charge, not strict site specificity, achieves phototransduction deactivation

et al. 2020

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Melanopsin is a visual pigment expressed in a small subset of ganglion cells in the mammalian retina known as intrinsically photosensitive retinal ganglion cells (ipRGCs) and is implicated in regulating non-image forming functions such as circadian photoentrainment and pupil constriction and contrast sensitivity in image formation. Mouse melanopsin's Carboxyterminus (C-terminus) possesses 38 serine and threonine residues, which can potentially serve as phosphorylation sites for a G-protein Receptor Kinase (GRK) and be involved in the deactivation of signal transduction. Previous studies suggest that S388, T389, S391, S392, S394, S395 on the proximal region of the C-terminus of mouse melanopsin are necessary for melanopsin deactivation. We expressed a series of mouse melanopsin C-terminal mutants in HEK293 cells and using calcium imaging, and we found that the necessary cluster of six serine and threonine residues, while being critical, are insufficient for proper melanopsin deactivation. Interestingly, the additional six serine and threonine residues adjacent to the required six sites, in either proximal or distal direction, are capable of restoring wild-type deactivation of melanopsin. These findings suggest an element of plasticity in the molecular basis of melanopsin phosphorylation and deactivation. In addition, C-terminal chimeric mutants and molecular modeling studies support the idea that the initial steps of deactivation and β-arrestin binding are centered around these critical phosphorylation sites (S388-S395). The degree of functional versatility described in this study, along with ipRGC biophysical heterogeneity and the possible use of multiple signal transduction cascades, might contribute to the diverse ipRGC light responses for use in non-image and image forming behaviors, even though all six sub types of ipRGCs express the same melanopsin gene OPN4.

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Section: Plos Onementioning

confidence: 99%

Melanopsin Carboxy-terminus phosphorylation plasticity and bulk negative charge, not strict site specificity, achieves phototransduction deactivation

et al. 2020

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“…4D, bottom). Therefore, M6 RGCs are unlikely to transmit absolute luminance 219 information to the OPN, and any melanopsin-mediated current is likely only to have a 220 modulatory effect on M6 function as in ON alpha (M4) ipRGCs (Sonoda et al, 2018). 221 which increase spiking monotonically with increasing luminance (Clarke and Ikeda, 1985).…”

Section: Statistical Analysis 130mentioning

confidence: 99%

The Olivary Pretectal Nucleus Receives Visual Input of High Spatial Resolution

Levine¹,

Schwartz²

2020

Preprint

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1 In the mouse, retinal output is computed by over 40 distinct types of retinal ganglion cells 2 (RGCs) (Baden et al., 2016). Determining which of these many RGC types project to a 3 retinorecipient region is a key step in elucidating the role that region plays in visually-mediated 4 behaviors. Combining retrograde viral tracing and single-cell electrophysiology, we identify the 5 RGC types which project to the olivary pretectal nucleus (OPN), a major visual structure. We 6 find that retinal input to the OPN consists of a variety of intrinsically-photosensitive and 7 conventional RGC types, the latter a diverse set of mostly ON RGCs. Surprisingly, while the 8 OPN is most associated with the pupillary light reflex (PLR) pathway, requiring information 9 about absolute luminance, we show that the majority of the retinal input to the OPN is from 10 single cell type which transmits information unrelated to luminance. This ON-transient RGC 11accounts for two-thirds of the input to the OPN, and responds to small objects across a wide 12 range of speeds. This finding suggests a role for the OPN in visually-mediated behaviors 13 beyond the PLR. 14 Significance statement 15The olivary pretectal nucleus is a midbrain structure which receives direct input from retinal 16 ganglion cells (RGC), and modulates pupil diameter in response to changing absolute light 17level. In the present study, we combine viral tracing and electrophysiology to identify the RGC 18 types which project to the OPN. Surprisingly, the majority of its input comes from a single type 19 which does not encode absolute luminance, but instead responds to small objects across a wide 20 range of speeds. These findings are consistent with a role for the OPN apart from pupil control 21 and suggest future experiments to elucidate its full role in visually-mediated behavior. 22 157

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“…Unlike rods and cones, melanopsin in M1-type ipRGCs signal through a Gαq-mediated pathway that leads to the opening of TRPC6/7 channels (15, 16, 17, 18). Recent studies analyzing the M4 ipRGC subtype suggest that melanopsin in these cells signals either through the Gαq transduction cascade (19) or through a cyclic-nucleotide cascade and the opening of HCN-channels (20).…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, ipRGC light responses are sluggish (single flash responses can persist across minutes) (38) compared to rapid photoresponses observed in rod and cone photoreceptors (these cells can respond in a precise manner to millisecond-scale light flashes). Melanopsin Gαq signal transduction has been shown to be re-purposed to modulate leak potassium channels (rather than activating phospholipase C) or could possibly couple to another G-protein to stimulate cyclic nucleotide signal transduction, in M4-type ipRGCs (19, 20). Within the M1-type population, there is a striking heterogeneity in the light responses, where there is a mixture of cells that optimally respond to certain irradiances or respond in a linear fashion in response to increasing irradiance, thus allowing for this M1 population to encode for a breadth of light intensities (39).…”

Section: Introductionmentioning

confidence: 99%

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

Valdez-Lopez

Petr

Donohue³

et al. 2020

Preprint

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27Melanopsin, an atypical vertebrate visual pigment, mediates non-image forming light responses 28 including circadian photoentrainment and pupillary light reflexes, and contrast detection for image 29formation. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), are 30 characterized by sluggish activation and deactivation of their light responses. The molecular determinants 31 of mouse melanopsin's deactivation have been characterized (i.e. C-terminal phosphorylation and β-32 arrestin binding), but a detailed analysis of melanopsin's activation is lacking. We propose that an 33 extended 3 rd cytoplasmic loop is adjacent to the proximal C-terminal region of mouse melanopsin in the 34 inactive conformation which is stabilized by ionic interaction of these two regions. This model is 35supported by site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy of 36 melanopsin, the results of which suggests a high degree of steric freedom at the 3 rd cytoplasmic loop, 37which is increased upon C-terminus truncation, supporting the idea that these two regions are close in 3-38 dimensional space in wild-type melanopsin. To test for a functionally critical C-terminal conformation, 39 calcium imaging of melanopsin mutants including a proximal C-terminus truncation (at residue 365) and 40 proline mutation of this proximal region (H377P, L380P, Y382P) delayed melanopsin's activation rate. 41Mutation of all potential phosphorylation sites, including a highly conserved tyrosine residue (Y382), into 42 alanines also delayed the activation rate. A comparison of mouse melanopsin with armadillo 43 melanopsin-which has substitutions of various potential phosphorylation sites and a substitution of the 44 conserved tyrosine-indicates that substitution of these potential phosphorylation sites and the tyrosine 45 residue result in dramatically slower activation kinetics, a finding that also supports the role of 46 phosphorylation in signaling activation. We therefore propose that melanopsin's C-terminus is proximal 47 to intracellular loop 3 and C-terminal phosphorylation permits the ionic interaction between these two 48 regions, thus forming a stable structural conformation that is critical for initiating G-protein signaling. 49 50 STATEMENT OF SIGNIFICANCE 51 Melanopsin Structure and Activation 3 Melanopsin is an important visual pigment in the mammalian retina that mediates non-image 52forming responses such as circadian photoentrainment and pupil constriction, and supports contrast 53 detection for image formation. In this study, we detail two critical structural features of mouse 54 melanopsin-its 3 rd cytoplasmic loop and C-terminus-that are important in the activation of 55 melanopsin's light responses. Furthermore, we propose that these two regions directly participate in 56 coupling mouse melanopsin to its G-protein. These findings contribute to further understanding of GPCR-57 G-protein coupling, and given recent findings suggesting flexibility of melanopsin signal trans...

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Melanopsin Phototransduction Is Repurposed by ipRGC Subtypes to Shape the Function of Distinct Visual Circuits

Cited by 95 publications

References 70 publications

Melanopsin Carboxy-terminus phosphorylation plasticity and bulk negative charge, not strict site specificity, achieves phototransduction deactivation

Melanopsin Carboxy-terminus phosphorylation plasticity and bulk negative charge, not strict site specificity, achieves phototransduction deactivation

The Olivary Pretectal Nucleus Receives Visual Input of High Spatial Resolution

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

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