Interactions with PDZ Proteins Are Required for L-Type Calcium Channels to Activate cAMP Response Element-Binding Protein-Dependent Gene Expression

Abstract

After brief periods of heightened stimulation, calcium entry through L-type calcium channels leads to activation of the transcription factor cAMP response element-binding protein (CREB) and CRE-dependent transcription. Many of the details surrounding the mechanism by which L-type calcium channels are privileged in signaling to CREB, to the exclusion of other calcium entry pathways, has remained unclear. We hypothesized that the PDZ interaction sequence contained within the last four amino acids of the calcium channel

The PDZ Motif of the α1C Subunit Is Not Required for Surface Trafficking and Adrenergic Modulation of CaV1.2 Channel in the Heart

“…The role for the PDZ ligand domain in the heart is unknown. Cultured neurons transfected, using a Ca 2ϩ phosphate technique, with ␣ 1C lacking the PDZ ligand domain exhibited attenuated cAMP-response element-binding protein responses, indicating an important role for the PDZ ligand motif in the subcellular localization of ␣ 1C in neurons (21). Although adenoviruses have been used to express Ca V 1.2 subunits in cardiomyocytes (35,36), creation of adenoviruses encoding ␣ 1C is difficult because of the ␣ 1C insert size and because viral infection requires that cardiomyocytes be cultured for extended periods.…”

“…1). To efficiently activate cAMP-response element-binding protein and gene expression in hippocampal neurons, interactions between the ␣ 1C subunit and proteins with a PDZ domain have been shown to be required (21), although the PDZ motif is not required for correct subcellular distribution or membrane expression of Ca V 1.2 in dendrites (22). The role of the PDZ ligand motif of Ca V 1.2, therefore, differs from that of Ca V 1.3, which depends on its PDZ motif for association with Shank and insertion into the postsynaptic membrane (23), and Ca V 2.2, which depends on its PDZ motif for insertion into the presynaptic space (24).…”

Ca2+-Dependent, Stimulus-Specific Modulation of the Plasma Membrane Ca2+Pump in Hippocampal Neurons

“…1999; Weick et al 2003). We speculate that localization of PMCAs to specific Ca 2ϩ microdomains enables selective modulation of Ca 2ϩ pumps to serve local needs.…”

“…We speculate that the various stimuli differentially activate rapid, Ca 2ϩ -dependent processes that modulate PMCA susceptibility to C-terminus cleavage by calpain. The differential localization of Ca 2ϩ -sensitive signaling cascades at NMDA receptor versus VGCC by attachment to scaffolding proteins is well documented (Sattler et al 1999;Weick et al 2003).…”

“…For example, NMDAevoked Ca 2ϩ entry activates nitric oxide synthase (NOS), whereas a comparable depolarization-induced increase in cellular [Ca 2ϩ ] i did not. This selectivity resulted from the localization of NOS close to the mouth of the NMDA-gated ion channel such that it experienced a [Ca 2ϩ ] i increase much higher than the global increase that spread throughout the cytoplasm (Sattler et al 1999;Weick et al 2003). The arrangement of Ca 2ϩ sensitive signaling molecules on scaffoldings close to the mouth of Ca 2ϩ permeable ion channels accounts for the selective activation of nuclear factor of activated T-cells (NFAT) by Ca 2ϩ entry via L-type Ca 2ϩ channels (Sattler et al FIG. 6.…”