Abstract
cAMP is a critical second messenger mediating activity-dependent neuronal survival and neurite growth. We investigated the expression and function of the soluble adenylyl cyclase (sAC, ADCY10) in CNS retinal ganglion cells (RGCs). We found sAC protein expressed in multiple RGC compartments including the nucleus, cytoplasm and axons. sAC activation increased cAMP above the level seen with transmembrane adenylate cyclase (tmAC) activation. Electrical activity and bicarbonate, both physiologic sAC activators, significantly increased survival and axon growth, whereas pharmacologic or siRNA-mediated sAC inhibition dramatically decreased RGC survival and axon growth in vitro, and survival in vivo. Conversely, RGC survival and axon growth were unaltered in RGCs from AC1/AC8 double knock-out mice or after specifically inhibiting tmACs. These data identify a novel sAC-mediated cAMP signaling pathway regulating RGC survival and axon growth, and suggest new neuroprotective or regenerative strategies based on sAC modulation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenylyl Cyclases / deficiency
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Adenylyl Cyclases / genetics
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Adenylyl Cyclases / metabolism*
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Analysis of Variance
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Animals
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Animals, Newborn
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Axons / drug effects
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Axons / physiology*
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Bicarbonates / pharmacology
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Cell Survival / drug effects
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Cell Survival / genetics
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Cell Survival / physiology
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Cells, Cultured
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Dose-Response Relationship, Drug
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Electric Stimulation
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Electroporation / methods
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Enzyme Inhibitors / pharmacology
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Enzyme-Linked Immunosorbent Assay
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Estradiol / analogs & derivatives
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Estradiol / pharmacology
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Extracellular Fluid / metabolism
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / genetics
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Guanine Nucleotide Exchange Factors / metabolism
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Intravitreal Injections
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Mice
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Mice, Knockout
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Optic Nerve Injuries / pathology
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RNA, Messenger / metabolism
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RNA, Small Interfering / physiology
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Rats
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Rats, Sprague-Dawley
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Retina / cytology
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Retinal Ganglion Cells / cytology*
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Retinal Ganglion Cells / drug effects
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Retinal Ganglion Cells / physiology*
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Time Factors
Substances
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Bicarbonates
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Enzyme Inhibitors
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Guanine Nucleotide Exchange Factors
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RNA, Messenger
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RNA, Small Interfering
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Rapgef3 protein, rat
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Rapgef4 protein, rat
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Estradiol
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2-hydroxyestradiol
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinases
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Adenylyl Cyclases
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adenylyl cyclase 1
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adenylyl cyclase 8