Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling
Nicholas C. Vierra, Luisa Ribeiro‐Silva, Michael Kirmiz, Deborah van der List, Pradeep Bhandari, Olivia A. Mack, James R. Carroll, Elodie Le Monnier, Sue A. Aicher, Ryuichi Shigemoto, James S. Trimmer
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 Ca 2+ 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 Ca 2+ signaling machinery to support Ca 2+ 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 Ca 2+ , allowing conversion of information encoded in electrical signals into biochemical changes universally recognized throughout the cell.