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Invest Ophthalmol Vis Sci. 2012 Sep 19;53(10):6355-69.

Mislocalized opsin and cAMP signaling: a mechanism for sprouting by rod cells in retinal degeneration.

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  • 1Department of Neurology and Neuroscience, New Jersey Medical School–University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.

Abstract

PURPOSE:

In human retinal degeneration, rod photoreceptors reactively sprout neurites. The mechanism is unknown in part because of the paucity of animal models displaying this feature of human pathology. We tested the role of cAMP and opsin in sprouting by tiger salamander rod cells, photoreceptors that can produce reactive growth.

METHODS:

In vitro systems of isolated photoreceptor cells and intact neural retina were used. cAMP signaling was manipulated with nucleotide analogues, enzyme stimulators, agonists for adenosine and dopamine receptors, and the opsin agonist, β-ionone. Levels of cAMP were determined by radioimmunoassay, and protein levels by Western blot and quantitative immunocytochemistry. Neuritic growth was assayed by image analysis and conventional and confocal microscopy.

RESULTS:

cAMP analogues and stimulation of adenylyl cyclase (AC) directly or through G-protein-coupled receptors resulted in significant increases in neuritic growth of isolated rod, but not cone, cells. The signaling pathway included protein kinase A (PKA) and phosphorylation of the transcription factor cAMP response element-binding protein (pCREB). Opsin, a G-linked receptor, is present throughout the plasmalemma of isolated cells; its activation also induced sprouting. In neural retina, rod sprouting was significantly increased by β-ionone with concomitant increases in cAMP, pCREB, and synaptic proteins. Notably, opsin stimulated sprouting only when mislocalized to the plasmalemma of the rod cell body.

CONCLUSIONS:

cAMP causes neuritic sprouting in rod, but not cone, cells through the AC-PKA-CREB pathway known to be associated with synaptic plasticity. We propose that in retinal disease, mislocalized rod opsin gains access to cAMP signaling, which leads to neuritic sprouting.

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