Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling

Nicholas C. Vierra (), Luisa Ribeiro-Silva, Michael Kirmiz, Deborah List, Pradeep Bhandari, Olivia A. Mack, James Carroll, Elodie Monnier, Sue A. Aicher, Ryuichi Shigemoto and James S. Trimmer ()
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Nicholas C. Vierra: University of California Davis School of Medicine
Luisa Ribeiro-Silva: University of California Davis School of Medicine
Michael Kirmiz: University of California Davis School of Medicine
Deborah List: University of California Davis School of Medicine
Pradeep Bhandari: Institute of Science and Technology Austria (ISTA)
Olivia A. Mack: Oregon Health & Science University
James Carroll: Oregon Health & Science University
Elodie Monnier: Institute of Science and Technology Austria (ISTA)
Sue A. Aicher: Oregon Health & Science University
Ryuichi Shigemoto: Institute of Science and Technology Austria (ISTA)
James S. Trimmer: University of California Davis School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Junctions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are specialized membrane contacts ubiquitous in eukaryotic cells. Concentration of intracellular signaling machinery near ER-PM junctions allows these domains to serve critical roles in lipid and Ca2+ signaling and homeostasis. Subcellular compartmentalization of protein kinase A (PKA) signaling also regulates essential cellular functions, however, no specific association between PKA and ER-PM junctional domains is known. Here, we show that in brain neurons type I PKA is directed to Kv2.1 channel-dependent ER-PM junctional domains via SPHKAP, a type I PKA-specific anchoring protein. SPHKAP association with type I PKA regulatory subunit RI and ER-resident VAP proteins results in the concentration of type I PKA between stacked ER cisternae associated with ER-PM junctions. This ER-associated PKA signalosome enables reciprocal regulation between PKA and Ca2+ signaling machinery to support Ca2+ influx and excitation-transcription coupling. These data reveal that neuronal ER-PM junctions support a receptor-independent form of PKA signaling driven by membrane depolarization and intracellular Ca2+, allowing conversion of information encoded in electrical signals into biochemical changes universally recognized throughout the cell.

Date: 2023
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DOI: 10.1038/s41467-023-40930-6

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