Competition between α-actinin and Ca2+-Calmodulin Controls Surface Retention of the L-type Ca2+ Channel CaV1.2

Abstract

SUMMARY Regulation of neuronal excitability and cardiac excitation-contraction coupling requires 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 CaV1.2 subunit, to foster its surface expression. Disruption of α-actinin function by dominant negative or shRNA constructs reduces CaV1.2 surface localization in HEK293 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 CaV1.2 from spines. Coexpression of a Ca2+-binding deficient calmodulin mutant does not affect basal CaV1.2 surface expression, but inhibits its internalization upon Ca2+ influx. We conclude that α-actinin stabilizes CaV1.2 at the plasma membrane, and that its displacement by Ca2+-calmodulin induces Ca2+-induced endocytosis of CaV1.2, thus providing an important negative feedback mechanism for Ca2+ influx.

CaMKII: Claiming Center Stage in Postsynaptic Function and Organization

“…As BAPTA but not EGTA is fast enough to intercept Ca 2+ close to the channel mouth to interfere with its signaling to nearby Ca 2+ target sites, these results suggest once more that depolarization-induced Ca 2+ influx activates CaMKII molecules that reside within nanodomains near L-type channels (Neher, 1998) and are likely tethered to Ca v 1.2 (Hudmon et al, 2005b). Such a highly localized effect of Ca 2+ influx via L-type channels is also in agreement with most recent findings that stimulating hippocampal slices with glutamate leads to displacement of α-actinin from the IQ motif of Ca v 1.2, which otherwise anchors Ca v 1.2 at postsynaptic sites (Hall et al, 2013). This effect is blocked by inhibition of L-type channels, but not NMDARs, reflecting a highly localized Ca 2+ -mediated effect in spines within the immediate environment of Ca v 1.2 that cannot be mediated by robust Ca 2+ influx via NMDARs within the same spines.…”

Regulation of Cardiac L-Type Ca 2+ Channel Ca V 1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway

“…125 It seems that the rundown is not the opposite of the regular basal I Ca but the result of a collapse of the multiprotein complex within which the channel operates and of the phosphorylation-dephosphorylation balance of the channel or associated proteins.…”

Calcium Dependent Interaction of Calmodulin with the GlyT1 C-terminus

“…induced endocytosis and provides a negative feedback for Ca 2? influx [41]. Similarly CaM bound on KCNQ2 has also been reported to act as a Ca 2?…”

“…Calmodulin (CaM) is an important calcium sensor, which has been previously shown to interact with several membrane receptors [38][39][40][41]. Here we identified several amino acids located within or downstream of the SEC24 interaction motif of GlyT1, which are structurally important for the calcium dependent interaction of the transporter C-terminus with calmodulin in vitro.…”