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E. Townes-Anderson, J. Wang; Dopamine and Adenosine Affect Rod Cell Sprouting. Invest. Ophthalmol. Vis. Sci. 2009;50(13):6229.
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Rod cells sprout neurites with synaptic vesicle-filled varicosities in retinal diseases such as retinitis pigmentosa and after reattachment of detached retina. The mechanisms that cause sprouting are not well understood. We have shown that cGMP stimulates cone but inhibits rod cell sprouting in cell cultures. Rod cells in contrast seem to be stimulated by cAMP. Here we have tested whether changes in the activity of adenylyl cyclase (AC) can alter sprouting by isolated photoreceptors.
Cultures were prepared from adult salamanders, maintained for 4 hrs or 3 days, stained for rod opsin to distinguish rod from cone cells, and analyzed for neuritic growth by length of longest process and number of varicosities. Activity of the cAMP-dependent transcription factor CREB was determined by densitometry of pCREB immunolabel.
Forskolin (FSK, 10µM), an AC stimulator, increased process length of rod and cone cells after 3 days in vitro. PCREB immunolabel was increased after 4 hrs for rod (7-fold) and cone (3-fold) cells. FSK specifically enhanced synaptic protein expression, in Westerns of intact retina, by 4 hrs. To more physiologically manipulate cAMP levels, agonists to D2-4 and A2a receptors, quinpirole and CGS 21680 respectively, were applied at multiple doses to retinal cultures. Quinpirole (10µM), which inhibits AC, reduced rod cell process length and pCREB immunolabel at 3 days. CGS (20µM), which stimulates AC, increased process length and varicosity number at 3 days, and pCREB label beginning at 4 hrs up to 2 days in vitro. Dopamine and adenosine receptor agonists had no effect on cone cell growth or pCREB densitometry.
Although FSK, and therefore high levels of cAMP, promote cone cell sprouting, AC activity through binding of the A2a receptor increased rod cell sprouting exclusively, most likely through pCREB. CREB phosphorylation in turn may enhance synaptic protein synthesis. Inhibition of AC through dopamine decreased rod cell sprouting coincident with reduced pCREB. It is possible that the dopamine and adenosine neurotransmitter systems play a role in rod cell sprouting responses seen in retinal disease and reattachment.
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