Regulation of neuronal excitation-transcription coupling by Kv2.1-induced clustering of somatic L-type Ca2+ channels at ER-PM junctions.
Proc Natl Acad Sci U S A
; 118(46)2021 11 16.
Article
em En
| MEDLINE
| ID: mdl-34750263
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+ channel-dependent 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.
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MEDLINE
Assunto principal:
Transcrição Gênica
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Membrana Celular
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Canais de Cálcio Tipo L
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Retículo Endoplasmático
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Canais de Potássio Shab
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Neurônios
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article