title: Competition between α-actinin and Ca²⁺-calmodulin controls surface retention of the L-type Ca²⁺ channel Ca(V)1.2.
abstract: Regulation of neuronal excitability and cardiac excitation-contraction coupling requires the proper localization of L-type Ca²⁺ channels. We show that the actin-binding protein α-actinin binds to the C-terminal surface targeting motif of α11.2, the central pore-forming Ca(V)1.2 subunit, in order to foster its surface expression. Disruption of α-actinin function by dominant-negative or small hairpin RNA constructs reduces Ca(V)1.2 surface localization in human embryonic kidney 293 and neuronal cultures and dendritic spine localization in neurons. We demonstrate that calmodulin displaces α-actinin from their shared binding site on α11.2 upon Ca²⁺ influx through L-type channels, but not through NMDAR, thereby triggering loss of Ca(V)1.2 from spines. Coexpression of a Ca²⁺-binding-deficient calmodulin mutant does not affect basal Ca(V)1.2 surface expression but inhibits its internalization upon Ca²⁺ influx. We conclude that α-actinin stabilizes Ca(V)1.2 at the plasma membrane and that its displacement by Ca²⁺-calmodulin triggers Ca²⁺-induced endocytosis of Ca(V)1.2, thus providing an important negative feedback mechanism for Ca²⁺ influx.
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Duane D
authors.initials: DD
authors.lastname: Hall
authors.forename: Shuiping
authors.initials: S
authors.lastname: Dai
authors.forename: Pang-Yen
authors.initials: PY
authors.lastname: Tseng
authors.forename: Zulfiqar
authors.initials: Z
authors.lastname: Malik
authors.forename: Minh
authors.initials: M
authors.lastname: Nguyen
authors.forename: Lucas
authors.initials: L
authors.lastname: Matt
authors.forename: Katrin
authors.initials: K
authors.lastname: Schnizler
authors.forename: Andrew
authors.initials: A
authors.lastname: Shephard
authors.forename: Durga P
authors.initials: DP
authors.lastname: Mohapatra
authors.forename: Fuminori
authors.initials: F
authors.lastname: Tsuruta
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Dolmetsch
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Christel
authors.forename: Amy
authors.initials: A
authors.lastname: Lee
authors.forename: Alain
authors.initials: A
authors.lastname: Burette
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Weinberg
authors.forename: Johannes W
authors.initials: JW
authors.lastname: Hell
mesh_terms: D000185:Actinin / Q000378:metabolism*; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D002147:Calmodulin; C419385:L-type calcium channel alpha(1C); D016194:Receptors, N-Methyl-D-Aspartate; D000185:Actinin