FUNCTIONAL ANALYSIS OF THE PHOTORECEPTOR RIM PROTEIN

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All vertebrate photoreceptors contain an outer segment, consisting of a dense stack of precisely aligned membranous discs. The reactions of visual transduction occur on the surfaces of these discs. Very little is known about the biochemical determinants of outer segment structure. By electron microscopic analysis, a critical event appears to be formation of the disc rim. A number of years ago, a high molecular weight, integral-membrane glycoprotein was identified with a distribution restricted to the rims of outer segment discs. This rim protein is the focus of the current proposal. We will utilize an integrated strategy of biochemical, cell biological, and genetic techniques to determine the function of the rim protein in photoreceptor outer segments. We have recently cloned the mRNA and gene encoding the rim protein in mouse and bovine retina. This study addresses the specific questions: (a) what is the domain structure and membrane topology of the rim protein? (b) is the rim protein responsible for the observed ultrastructural connections between the rims of adjacent discs? (c) alternatively, does it mediate the observed connections between the disc rim and the plasma membrane through interactions with the cytoskeleton? (d) if so, what cytoskeletal proteins are present in outer segments? (e) does the rim protein interact with the other known disc rim proteins, rds/peripherin and rom-I? (/)what additional outer segment proteins interact with the rim protein? g) what is the role of its light-dependent phosphorylation? (h) what is the phenotype that results from absence of the rim protein in developing and mature outer segments? and (i) are any of the human inherited retinal dystrophies caused by mutations in the rim protein gene?