title: AKAP-mediated feedback control of cAMP gradients in developing hippocampal neurons.
abstract: Cyclic AMP (cAMP) and protein kinase A (PKA), classical examples of spatially compartmentalized signaling molecules, are critical axon determinants that regulate neuronal polarity and axon formation, yet little is known about micro-compartmentalization of cAMP and PKA signaling and its role in developing neurons. Here, we revealed that cAMP forms a gradient in developing hippocampal neurons, with higher cAMP levels in more distal regions of the axon compared to other regions of the cell. Interestingly, this cAMP gradient changed according to the developmental stage and depended on proper anchoring of PKA by A-kinase anchoring proteins (AKAPs). Disrupting PKA anchoring to AKAPs increased the cAMP gradient in early-stage neurons and led to enhanced axon elongation. Our results provide new evidence for a local negative-feedback loop, assembled by AKAPs, for the precise control of a growth-stage-dependent cAMP gradient to ensure proper axon growth.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Kirill
authors.initials: K
authors.lastname: Gorshkov
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Sohum
authors.initials: S
authors.lastname: Mehta
authors.affiliation: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Ramamurthy
authors.affiliation: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Center for Metabolism and Obesity Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Departments of Neurology and Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Gabriele V
authors.initials: GV
authors.lastname: Ronnett
authors.affiliation: Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Orthopedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Feng-Quan
authors.initials: FQ
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D025461:Feedback, Physiological; D006624:Hippocampus / Q000166:cytology*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D054758:A Kinase Anchor Proteins; D000242:Cyclic AMP