The retina contains one of the best-studied G-protein coupled receptors (GPCR), the light-activated phototransduction cascade responsible for visual perception. As such it serves as a model for GPCR systems throughout the body, and yet there remain important unanswered questions about the feedback and modulation of GPCR signaling, especially as it affects termination of the cascade. The reliable shutoff is highly controlled in photoreceptors, and it establishes the temporal capabilities of the visual system. More importantly, photoreceptors can alter shutoff timing as an adaptation to changes in ambient illumination. These molecular events are understood in part, but further work is required to define the multiple mechanisms of adaptation. The first goal of this proposed research is to identify the conditions that elicit a newly discovered form of adaptation in rod photoreceptors and to ascertain the underlying mechanisms controlling it. This form of adaptation reveals a paradoxical hypersensitivity of our dim light photoreceptors following exposure to bright light. We propose to study this rod adaptation at cellular level as well as through clinical and behavioral tests in human subjects. This work will reveal new information about visual system adaptation during mesopic lighting conditions, the twice-daily twilight evolutionarily vital to bot the hunter and the hunted. Additionally, our efforts will provide a more thorough understanding of how the GPCR pathway can be modified to adapt to constant stimuli. Despite being the minority cell in the human visual system, cone photoreceptors have tremendous importance for daytime vision, spatial acuity, and color perception. At this point, there is a far better understanding of rod mechanisms, many of which do not directly translate to cone function. One important aspect that needs to be investigated is the immense adaptive range of cones and the speed with which they accomplish the task. Indeed, the temporal flicker resolution of cone vision measured behaviorally needs to be explained in more detail on the single cell level. A more complete understanding of cone function and adaptation will further not only the field of vision, but the entire field of neurobiology with respect to different GPCR signaling pathways.
This research addresses fundamental issues of rod and cone photoreceptor inactivation and adaptation;our experiments are designed to elucidate the mechanisms controlling the shut-off of the phototranduction cascade as they relate to short-term adaptation and the dynamic differences between how rods and cone photoreceptors function. The outcomes of this work directly respond to NEI's 2012 programmatic need to understand the molecular mechanisms and pathways in cone photoreceptors that have not been as extensively studied as rods. Finally, a clear understanding of the balance achieved between the signal generation cascade and the termination/recovery steps of phototransduction may ultimately be related to optimization of the cellular energy needs and the natural neuroprotective mechanisms of photoreceptors.
|McKeown, Alex S; Pitale, Priyamvada M; Kraft, Timothy W (2016) Signalling beyond photon absorption: extracellular retinoids and growth factors modulate rod photoreceptor sensitivity. J Physiol 594:1841-54|
|Lamb, Trevor D; Kraft, Timothy W (2016) Quantitative modeling of the molecular steps underlying shut-off of rhodopsin activity in rod phototransduction. Mol Vis 22:674-96|
|McKeown, Alex S; Kraft, Timothy W; Loop, Michael S (2015) Increased visual sensitivity following periods of dim illumination. Invest Ophthalmol Vis Sci 56:1864-71|
|McKeown, Alex S; Kraft, Timothy W (2014) Adaptive potentiation in rod photoreceptors after light exposure. J Gen Physiol 143:733-43|
|Clark, Molly E; Kraft, Timothy W (2012) Measuring rodent electroretinograms to assess retinal function. Methods Mol Biol 884:265-76|