Soluble adenylyl cyclase activity is necessary for retinal ganglion cell survival and axon growth.
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.
Bascom Palmer Eye Institute, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Raul G
RG
Corredor
Ephraim F
EF
Trakhtenberg
Wolfgang
W
Pita-Thomas
Xiaolu
X
Jin
Ying
Y
Hu
Jeffrey L
JL
Goldberg
D000262:Adenylyl Cyclases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D001639:Bicarbonates / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018274:Electroporation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D045604:Extracellular Fluid / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D058449:Intravitreal Injections; D051379:Mice; D018345:Mice, Knockout; D020221:Optic Nerve Injuries / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000166:cytology; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D001639:Bicarbonates; D004791:Enzyme Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C526973:Rapgef3 protein, rat; C531571:Rapgef4 protein, rat; D004958:Estradiol; C001390:2-hydroxyestradiol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1; C118292:adenylyl cyclase 8