All ETDs from UAB

Advisory Committee Chair

Timothy W Kraft

Advisory Committee Members

Lawrence C Sincich

Alecia K Gross

Lori L McMahon

Steven J Pittler

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

In the first step in light perception, rod and cone photoreceptors convert photon absorption into an electrical impulse that is transmitted through the visual pathway. While the biochemistry and the signaling physiology have largely been defined in dark-adapted, isolated mammalian rods, there are still unanswered questions regarding photoreceptor light adaptation processes that involve extracellular components. In particular, the proteins of the interphotoreceptor matrix have not been considered in the studies of rod signaling and adaptation. This thesis details a new form of light adaptation, now known as adaptive potentiation (AP), in which extracellular components act on rods to transiently increase the sensitivity of the phototransduction cascade. Chapter 2 outlines the discovery and characterization of the adaptation, with specific attention devoted to the light intensity and duration that elicits AP. Additional experiments reveal that the enzymatic action of insulin-like growth factor-1 receptor (IGF-1R), in conjunction with a tyrosine phosphatase, causes dephosphorylation of the rod cyclic nucleotide gated (CNG) channels during light exposure. Once dephosphorylated the CNG channels are more sensitive to signaling of the phototransduction cascade. As a result, the rods are hypersensitive to light for ~30 seconds after the conditioning light exposure. Chapter 3 adds to the number of molecular mechanisms of AP identified in Chapter 2, and implicates the all-trans retinol form of retinoid in signaling AP extracellularly. Physiological application of IGF-1 is also shown to be involved in the signaling of AP, further suggesting that the IGF-1R is involved in modulating channel sensitivity. Immunohistochemical analysis of the interphotoreceptor matrix reveals the presence of extracellular protein components that are adherent to the photoreceptor outer segments, even after the retinal pigment epithelium has been removed. Chapter 4 is an investigation of the perceptual impact of AP in human subjects. Conditioning light exposures, known to elicit AP in isolated retinas, were used to elicit AP in the peripheral retinas of our human subjects as they performed a psychophysical task. Reaction times to visual stimuli were used to measure subject sensitivity before and after conditioning light exposures. We found that 3-minute periods of conditioning illumination reliably decreased subject reaction times, indicating increased visual sensitivity. Measurements of cellular noise in single mouse rods also indicated that there is not a significant increase in noise following conditioning light exposures, and that the signal-to-noise ratio is therefore elevated. This finding supports the idea that increased rod sensitivity is not contaminated by an increase in noise, and that such enhanced rod signals are transmitted to the perceptual level in humans. Finally, Chapter 5 is a discussion of the strengths and weaknesses of each of the techniques that I used to record photoreceptor function.

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