title: CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation.
abstract: Ca2+-dependent facilitation (CDF) of voltage-gated calcium current is a powerful mechanism for up-regulation of Ca2+ influx during repeated membrane depolarization. CDF of L-type Ca2+ channels (Ca(v)1.2) contributes to the positive force-frequency effect in the heart and is believed to involve the activation of Ca2+/calmodulin-dependent kinase II (CaMKII). How CaMKII is activated and what its substrates are have not yet been determined. We show that the pore-forming subunit alpha(1C) (Ca(v)alpha1.2) is a CaMKII substrate and that CaMKII interaction with the COOH terminus of alpha1C is essential for CDF of L-type channels. Ca2+ influx triggers distinct features of CaMKII targeting and activity. After Ca2+-induced targeting to alpha1C, CaMKII becomes tightly tethered to the channel, even after calcium returns to normal levels. In contrast, activity of the tethered CaMKII remains fully Ca2+/CaM dependent, explaining its ability to operate as a calcium spike frequency detector. These findings clarify the molecular basis of CDF and demonstrate a novel enzymatic mechanism by which ion channel gating can be modulated by activity.
authors.affiliation: Department of Neurobiology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Hudmon
authors.forename: Howard
authors.initials: H
authors.lastname: Schulman
authors.forename: James
authors.initials: J
authors.lastname: Kim
authors.forename: Janet M
authors.initials: JM
authors.lastname: Maltez
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tsien
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D004558:Electric Stimulation; D004789:Enzyme Activation; D005260:Female; D020035:Holoenzymes / Q000502:physiology; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000502:physiology*; D008954:Models, Biological; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000502:physiology; D011817:Rabbits; D051381:Rats; D014982:Xenopus laevis
chemical_list: D020746:Calcium Channels, L-Type; D020035:Holoenzymes; D021122:Protein Subunits; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium