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

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 ar...

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Published in:The Journal of neuroscience 2003-04, Vol.23 (8), p.3446-3456
Main Authors: Weick, Jason P, Groth, Rachel D, Isaksen, Ann L, Mermelstein, Paul G
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Groth, Rachel D
Isaksen, Ann L
Mermelstein, Paul G
description 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 alpha1C (Ca(V)1.2) subunit [Val-Ser-Asn-Leu (VSNL)] is critical for L-type calcium channels (LTCs) to interact with the signaling machinery that triggers activity-dependent gene expression. To disrupt this interaction, hippocampal CA3-CA1 pyramidal neurons were transfected with DNA encoding for enhanced green fluorescent protein tethered to VSNL (EGFP-VSNL). EGFP-VSNL significantly attenuated L-type calcium channel-induced CREB phosphorylation and CRE-dependent transcription, although somatic calcium concentrations after stimulation remained unchanged. The effect of EGFP-VSNL was specific to the actions of L-type calcium channels, because CREB signaling after NMDA receptor stimulation remained intact. The importance of the PDZ interaction sequence was verified using dihydropyridine (DHP)-insensitive alpha1C subunits. Neurons transfected with alpha1C lacking the terminal five amino acids (DHP-LTCnoPDZ) exhibited attenuated CREB responses in comparison with cells expressing the full-length subunit (DHP-LTC). Collectively, these data suggest that localized calcium responses, regulated by interactions with PDZ domain proteins, are necessary for L-type calcium channels to effectively activate CREB and CRE-mediated gene expression.
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subjects Amino Acid Motifs - physiology
Animals
Calcium - metabolism
Calcium Channels, L-Type - metabolism
Cells, Cultured
Cyclic AMP Response Element-Binding Protein - metabolism
Gene Expression Regulation - physiology
Genes, Reporter
Hippocampus - cytology
Humans
Interleukin-16 - metabolism
Nerve Tissue Proteins - metabolism
Patch-Clamp Techniques
PDZ proteins
Phosphorylation
Protein Binding - physiology
Protein Structure, Tertiary - physiology
Protein Subunits - genetics
Protein Subunits - metabolism
Proteins - metabolism
Pyramidal Cells - cytology
Pyramidal Cells - metabolism
Rats
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - metabolism
Signal Transduction - physiology
Transfection
title Interactions with PDZ Proteins Are Required for L-Type Calcium Channels to Activate cAMP Response Element-Binding Protein-Dependent Gene Expression
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