title: Soluble adenylyl cyclase is necessary and sufficient to overcome the block of axonal growth by myelin-associated factors.
abstract: Neurons in the CNS do not regenerate following injury; regeneration is blocked by inhibitory proteins in myelin, such as myelin-associated glycoprotein (MAG). Elevating neuronal levels of the second messenger cAMP overcomes this blocked axonal outgrowth. One way to elevate cAMP is pretreating neurons with neurotrophins, such as brain-derived neurotrophic factor (BDNF). However, pleiotropic effects and poor bioavailability make exogenous administration of neurotrophins in vivo problematic; therefore, alternative targets must be considered. In neurons, two families of adenylyl cyclases synthesize cAMP, transmembrane adenylyl cyclases (tmACs), and soluble adenylyl cyclase (sAC). Here, we demonstrate that sAC is the essential source of cAMP for BDNF to overcome MAG-dependent inhibition of neurite outgrowth. Elevating sAC in rat and mouse neurons is sufficient to induce neurite outgrowth on myelin in vitro and promotes regeneration in vivo. These results suggest that stimulators of sAC might represent a novel therapeutic strategy to promote axonal growth and regeneration.
authors.affiliation: Department of Biological Sciences, Hunter College, New York, New York 10065, and Department of Pharmacology and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.affiliation: Department of Pharmacology and Stitch Radiation Oncology Department, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Stessin
authors.affiliation: Department of Biological Sciences, Hunter College, New York, New York 10065, and.
authors.forename: Aline
authors.initials: A
authors.lastname: Campana
authors.affiliation: Department of Biological Sciences, Hunter College, New York, New York 10065, and.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Hou
authors.affiliation: Department of Pharmacology and.
authors.forename: Elena
authors.initials: E
authors.lastname: Nikulina
authors.affiliation: Department of Pharmacology and.
authors.forename: Jochen
authors.identifier: http://orcid.org/0000-0002-3568-5869
authors.initials: J
authors.lastname: Buck
authors.affiliation: Department of Pharmacology and llevin@med.cornell.edu.
authors.forename: Lonny R
authors.initials: LR
authors.lastname: Levin
authors.affiliation: Department of Biological Sciences, Hunter College, New York, New York 10065, and.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Filbin
mesh_terms: D000262:Adenylyl Cyclases / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure*; D016466:CHO Cells; D049108:Cell Enlargement; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism* / Q000648:ultrastructure; D003412:Cricetulus; D004789:Enzyme Activation; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000378:metabolism*; D018992:Myelin-Associated Glycoprotein; D009416:Nerve Regeneration / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D012995:Solubility
chemical_list: D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D000262:Adenylyl Cyclases
keywords: BDNF; axonal regeneration; cAMP; soluble adenylyl cyclase