title: γCaMKII shuttles Ca²⁺/CaM to the nucleus to trigger CREB phosphorylation and gene expression.
abstract: Activity-dependent CREB phosphorylation and gene expression are critical for long-term neuronal plasticity. Local signaling at CaV1 channels triggers these events, but how information is relayed onward to the nucleus remains unclear. Here, we report a mechanism that mediates long-distance communication within cells: a shuttle that transports Ca(2+)/calmodulin from the surface membrane to the nucleus. We show that the shuttle protein is γCaMKII, its phosphorylation at Thr287 by βCaMKII protects the Ca(2+)/CaM signal, and CaN triggers its nuclear translocation. Both βCaMKII and CaN act in close proximity to CaV1 channels, supporting their dominance, whereas γCaMKII operates as a carrier, not as a kinase. Upon arrival within the nucleus, Ca(2+)/CaM activates CaMKK and its substrate CaMKIV, the CREB kinase. This mechanism resolves long-standing puzzles about CaM/CaMK-dependent signaling to the nucleus. The significance of the mechanism is emphasized by dysregulation of CaV1, γCaMKII, βCaMKII, and CaN in multiple neuropsychiatric disorders.
authors.affiliation: Department of Neuroscience and Physiology, Neuroscience Institute, NYU Langone Medical Center, New York, NY 10016, USA. Electronic address: mahuan@gmail.com.
authors.forename: Huan
authors.initials: H
authors.lastname: Ma
authors.affiliation: Centers for Therapeutic Innovation, Pfizer, 1700 Owens Street, San Francisco, CA 94158, USA.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Groth
authors.affiliation: Department of Neuroscience and Physiology, Neuroscience Institute, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
authors.affiliation: Department of Neuroscience and Physiology, Neuroscience Institute, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Emery
authors.affiliation: Department of Neuroscience and Physiology, Neuroscience Institute, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Boxing
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and Skirball Institute, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Esthelle
authors.initials: E
authors.lastname: Hoedt
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and Skirball Institute, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Guoan
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Pharmacology and Skirball Institute, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Neubert
authors.affiliation: Department of Neuroscience and Physiology, Neuroscience Institute, NYU Langone Medical Center, New York, NY 10016, USA. Electronic address: richard.tsien@nyumc.org.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tsien
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic
chemical_list: D015220:Calcium Channels; D002147:Calmodulin; D017362:Cyclic AMP Response Element-Binding Protein; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium