Journal Article

Molecular determinants of response kinetics of mouse M1 intrinsically-photosensitive retinal ganglion cells

Ren, Xiaozhi, Sheng, Yanghui, Chen, Lujing, Yau, King-Wai, Jiang, Zheng

2021

Overview

Intrinsically-photosensitive retinal ganglion cells (ipRGCs) are non-rod/non-cone retinal photoreceptors expressing the visual pigment, melanopsin, to detect ambient irradiance for various non-image-forming visual functions. The M1-subtype, amongst the best studied, mediates primarily circadian photoentrainment and pupillary light reflex. Their intrinsic light responses are more prolonged than those of rods and cones even at the single-photon level, in accordance with the typically slower time course of non-image-forming vision. The short (OPN4S) and long (OPN4L) alternatively-spliced forms of melanopsin proteins are both present in M1-ipRGCs, but their functional difference is unclear. We have examined this point by genetically removing the Opn4 gene ( Opn4 −/− ) in mouse and re-expressing either OPN4S or OPN4L singly in Opn4 −/− mice by using adeno-associated virus, but found no obvious difference in their intrinsic dim-flash responses. Previous studies have indicated that two dominant slow steps in M1-ipRGC phototransduction dictate these cells’ intrinsic dim-flash-response kinetics, with time constants (τ 1 and τ 2 ) at room temperature of ~ 2 s and ~ 20 s, respectively. Here we found that melanopsin inactivation by phosphorylation or by β-arrestins may not be one of these two steps, because their genetic disruptions did not prolong the two time constants or affect the response waveform. Disruption of GAP (GTPase-Activating-Protein) activity on the effector enzyme, PLCβ4, in M1-ipRGC phototransduction to slow down G-protein deactivation also did not prolong the response decay, but caused its rising phase to become slightly sigmoidal by giving rise to a third time constant, τ 3 , of ~ 2 s (room temperature). This last observation suggests that GAP-mediated G-protein deactivation does partake in the flash-response termination, although normally with a time constant too short to be visible in the response waveform.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/378 / 631/80/86 / Animals / beta-Arrestins - chemistry / Circadian Rhythm - physiology / Circadian rhythms / Cones / Deactivation / Dependovirus / Humanities and Social Sciences / Inactivation / Intravitreal Injections / Kinetics / Light / Light effects / Light Signal Transduction / Melanopsin / Mice / Mice, Transgenic / multidisciplinary / Mutation / Neurosciences / Phospholipase C / Phosphorylation / Photopigments / Photoreceptors / Phototransduction / Proteins / Retina / Retinal Cone Photoreceptor Cells - metabolism / Retinal ganglion cells / Retinal Ganglion Cells - metabolism / Rod Opsins - chemistry / Science / Science (multidisciplinary) / Signal Transduction / Vision, Ocular