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

Abstract

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
Volume118
Issue number46
DOIs
StatePublished - Nov 16 2021

Keywords

  • 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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