Regulation of neuronal excitation-transcription coupling by Kv2.1-induced clustering of somatic L-type Ca2+ channels at ER-PM junctions

Nicholas C. Vierra, Samantha C. O'Dwyer, Collin Matsumoto, L. Fernando Santana, James S. Trimmer

Research output: Contribution to journalArticlepeer-review


In mammalian brain neurons, membrane depolarization leads to voltage-gated Ca2+ channel-mediated Ca2+ influx that triggers diverse cellular responses, including gene expression, in a process termed excitation-transcription coupling. Neuronal L-type Ca2+ channels, which have prominent populations on the soma and distal dendrites of hippocampal neurons, play a privileged role in excitation-transcription coupling. The voltage-gated K+ channel Kv2.1 organizes signaling complexes containing the L-type Ca2+ channel Cav1.2 at somatic endoplasmic reticulum-plasma membrane junctions. This leads to enhanced clustering of Cav1.2 channels, increasing their activity. However, the downstream consequences of the Kv2.1-mediated regulation of Cav1.2 localization and function on excitation-transcription coupling are not known. Here, we have identified a region between residues 478 to 486 of Kv2.1's C terminus that mediates the Kv2.1-dependent clustering of Cav1.2. By disrupting this Ca2+ channel association domain with either mutations or with a cell-penetrating interfering peptide, we blocked the Kv2.1-mediated clustering of Cav1.2 at endoplasmic reticulum-plasma membrane junctions and the subsequent enhancement of its channel activity and somatic Ca2+ signals without affecting the clustering of Kv2.1. These interventions abolished the depolarization-induced and L-type Ca2+ channeldependent phosphorylation of the transcription factor CREB and the subsequent expression of c-Fos in hippocampal neurons. Our findings support a model whereby the Kv2.1-Ca2+ channel association domain-mediated clustering of Cav1.2 channels imparts a mechanism to control somatic Ca2+ signals that couple neuronal excitation to gene expression.

Original languageEnglish (US)
Article numbere2110094118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number46
StatePublished - Nov 16 2021


  • Calcium signaling
  • Excitation-transcription coupling
  • Membrane contact sites
  • Voltage-gated calcium channels
  • Voltage-gated potassium channels

ASJC Scopus subject areas

  • General


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