title: CaMKIIβ-mediated LIM-kinase activation plays a crucial role in BDNF-induced neuritogenesis.
abstract: LIM-kinase 1 (LIMK1) regulates actin cytoskeletal reorganization by phosphorylating and inactivating actin-depolymerizing factor and cofilin. We examined the role of LIMK1 in brain-derived neurotrophic factor (BDNF)-induced neuritogenesis in primary-cultured rat cortical neurons. Knockdown of LIMK1 or expression of a kinase-dead LIMK1 mutant suppressed BDNF-induced enhancement of primary neurite formation. By contrast, expression of an active form of LIMK1 promoted primary neuritogenesis in the absence of BDNF. BDNF-induced neuritogenesis was inhibited by KN-93, an inhibitor of Ca(2+) /calmodulin-dependent protein kinases (CaMKs), but not by STO-609, an inhibitor of CaMK-kinase (CaMKK). CaMKK activity is required for the activation of CaMKI and CaMKIV, but not CaMKII, which suggests that CaMKII is principally involved in BDNF-induced enhancement of neuritogenesis. Knockdown of CaMKIIβ, but not CaMKIIα, suppressed BDNF-induced neuritogenesis. Active CaMKIIβ promoted neuritogenesis, and this promotion was inhibited by knockdown of LIMK1, indicating that CaMKIIβ is involved in BDNF-induced neuritogenesis via activation of LIMK1. Furthermore, in vitro kinase assays revealed that CaMKIIβ phosphorylates LIMK1 at Thr-508 in the kinase domain and activates the cofilin-phosphorylating activity of LIMK1. In summary, these results suggest that CaMKIIβ-mediated activation of LIMK1 plays a crucial role in BDNF-induced enhancement of primary neurite formation.
authors.affiliation: Department of Biomolecular Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi, 980-8578, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Saito
authors.forename: Ken
authors.initials: K
authors.lastname: Miyajima
authors.forename: Junichi
authors.initials: J
authors.lastname: Akatsuka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kondo
authors.forename: Toshiya
authors.initials: T
authors.lastname: Mashiko
authors.forename: Tai
authors.initials: T
authors.lastname: Kiuchi
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ohashi
authors.forename: Kensaku
authors.initials: K
authors.lastname: Mizuno
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D054461:Lim Kinases / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D019208:Brain-Derived Neurotrophic Factor; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D054461:Lim Kinases; D013449:Sulfonamides; C581829:Camk2n1 protein, rat; C072105:KN 93; D000096926:Benzenesulfonamides; C579455:BDNF protein, human; C515894:Limk1 protein, rat