Regulation of Postsynaptic Stability by the L-type Calcium Channel CaV1.3 and its Interaction with PDZ Proteins

Abstract

Alterations in dendritic spine morphology and postsynaptic structure are a hallmark of neurological disorders. Particularly spine pruning of striatal medium spiny neurons and aberrant rewiring of corticostriatal synapses have been associated with the pathology of Parkinson's disease and LDOPA induced dyskinesia, respectively. Owing to its low activation threshold the neuronal L-type calcium channel CaV1.3 is particularly critical in the control of neuronal excitability and thus in the calcium-dependent regulation of neuronal functions. CaV1.3 channels are located in dendritic spines and contain a C-terminal class 1 PDZ domain-binding sequence. Until today the postsynaptic PDZ domain proteins shank, densin-180, and erbin have been shown to interact with CaV1.3 channels and to modulate their current properties. Interestingly experimental evidence suggests an involvement of all three PDZ proteins as well as CaV1.3 itself in regulating dendritic and postsynaptic morphology. Here we briefly review the importance of CaV1.3 and its proposed interactions with PDZ proteins for the stability of dendritic spines. With a special focus on the pathology associated with Parkinson's disease, we discuss the hypothesis that CaV1.3 L-type calcium channels may be critical modulators of dendritic spine stability.

Fig. (1)

Model of the Ca_V1.3 signalosome in the membrane of dendritic spines: Shank proteins (shank1/3) bind to the distal C-terminus of Ca_V1.3 channels with their PDZ domain. Shank acts as scaffold for the association of metabotropic glutamate receptors via homer (mGluR, homer), AMPA receptors (GluA), and likely also for D2 dopamine receptors (D2-R) and calcineurin (PP2B). In striatal medium spiny neurons Ca_V1.3 activity is suppressed by D2-R mediated inhibition. In Parkinson’s disease dopamine depletion may thus increase Ca_V1.3 calcium influx, thereby destabilize the shank-Ca_V1.3 interaction and allow the PDZ domains of densin-180 and erbin to compete for binding to the Ca_V1.3 C-terminus. Subsequently erbin and densin induce alterations to dendritic spine morphology by contributing to the surface expression of AMPA receptors via the transmembrane AMPA-R regulatory proteins (TARP) γ2 (γ) and by regulating the postsynaptic localization of CaMKII and δ-catenin. Consequently increased calcium influx can activate the transcription factor myocyte enhancer factor 2 (MEF2) and regulate expression of genes involved in dendritic spine growth such as CaMKII and δ-catenin.