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Johannes Hell"α-Actinin Anchors Cav1.2 in dendritic spines in a Ca2+/CaM-sensitive Manner"

Abstract :

Proper localization of L-type Ca2+ channels is necessary for regulation of excitability in brain and excitation-contraction coupling in heart.
Full L-type channel activity requires an intact actin cytoskeleton. 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, regulating 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. 

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 internalization upon Ca2+ influx. 

We conclude that α-actinin stabilizes CaV1.2 at the plasma membrane, and its displacement by Ca2+-calmodulin induces Ca2+-induced endocytosis of CaV1.2, thus providing an important negative feedback mechanism for Ca2+ influx.

Selected publications

STriatal-enriched protein tyrosine phosphatase (STEP) regulates Pyk2 activity. Xu J, Kurup P, Bartos JA, Patriarchi T, Hell JW, Lombroso PJ.J Biol Chem. 2012 Apr 27. [Epub ahead of print]

β2-Adrenergic receptor supports prolonged theta tetanus-induced LTP. Qian H, Matt L, Zhang M, Nguyen M, Patriarchi T, Koval OM, Anderson ME, He K, Lee HK, Hell JW. J Neurophysiol. 2012 May;107(10):2703-12. Epub 2012 Feb 15.

CaMKII binding to GluN2B is critical during memory consolidation. Halt AR, Dallapiazza RF, Zhou Y, Stein IS, Qian H, Juntti S, Wojcik S, Brose N, Silva AJ, Hell JW. EMBO J. 2012 Jan 10;31(5):1203-16. doi: 10.1038/emboj.2011.482.

Thermodynamic linkage between calmodulin domains binding calcium and contiguous sites in the C-terminal tail of Ca(V)1.2. Evans TI, Hell JW, Shea MA. Biophys Chem. 2011 Nov;159(1):172-87. Epub 2011 Jun 24.

Role of the CaMKII/NMDA receptor complex in the maintenance of synaptic strength. Sanhueza M, Fernandez-Villalobos G, Stein IS, Kasumova G, Zhang P, Bayer KU, Otmakhov N, Hell JW, Lisman J.
J Neurosci. 2011 Jun 22;31(25):9170-8.

Laurent Groc de l'IINS