There have been great advances over the past 30-40 years in understanding how light initiates vision in the rod and cone photoreceptors of the eye. Not only is the sequence of events in this process known, but the genes coding for the key phototransduction proteins have also been cloned. Mutations of many of these genes are found to be associated with various vision-impairing diseases. Phototransduction starts with the visual pigment. Several years ago, we made major advances by showing that the dark spontaneous activity of rod and cone pigments indeed comes from canonical isomerization of these pigments albeit being driven by thermal instead of light energy. We developed a theory able to predict quantitatively the 107-fold range in thermal activity across rod and cone pigments in the visible spectrum. Our theory as originally developed describes very successfully the behavior of canonical rod and cone pigments, but we have now found it to be equally applicable to a non-canonical, hybrid pigment with both rod-pigment-like and cone-pigment-like properties.
In Aim 1, we propose to check the theory against several unusual native pigments and also a disease-causing mutant pigment for testing the theory's overall predictive power. Separately, the first step of signal amplification in rod phototransduction consists of a large number of downstream G protein molecules being activated by each photoexcited rhodopsin, with the amplification factor traditionally believed to be ~1,000, but now under debate.
In Aim 2, we shall evaluate directly the true amplification value in situ. Upon light off, phototransduction needs to terminate. The inactivation of photoexcited rhodopsin is initiated by its phosphorylation followed quickly by the binding of the capping protein, arrestin, which translocates massively to the rod outer segment from the inner segment, cell body and synaptic terminal in bright light.
In Aim 3, we shall examine the signaling underlying this arrestin translocation. Finally, for short Aim 4, we shall examine a potential mechanism whereby the ??-subunits of rod transducin may contribute to the deactivation of the cGMP-phosphodiesterase, the enzyme that is activated by transducin-? and hydrolyzes cGMP to produce the hyperpolarizing light response. Sorting out the above questions will help understand not only normal photoreceptor physiology, but also the pathophysiology underlying disease conditions.
The studies proposed in this application will enhance our understanding of phototransduction in retinal rods and cones. Any new information derived from these studies will be highly relevant to our knowledge about the normal and diseased states in human vision.
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