Interactions with PDZ proteins are required for L-type calcium channels to activate cAMP response element-binding protein-dependent gene expression

Jason P. Weick, Rachel D. Groth, Ann L. Isaksen, Paul G. Mermelstein

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

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 α1C (CaV1.2) 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 a1C subunits. Neurons transfected with a1C 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.

Original languageEnglish (US)
Pages (from-to)3446-3456
Number of pages11
JournalJournal of Neuroscience
Volume23
Issue number8
DOIs
StatePublished - Apr 15 2003

Keywords

  • A
  • CIPP
  • CREB
  • Ca1.2
  • L-type calcium channel
  • NFAT
  • NIL-16
  • NMDA

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