biostudies-literaturePeng GENIBIB NIH HHSNIDA NIH HHSNHLBI NIH HHSNIMH NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on Drug AbuseU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood InstituteU.S. Department of Health & Human Services | NIH | National Institute of Mental HealthU.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and BioengineeringAmerican Heart AssociationNINDS NIH HHSNCI NIH HHSNIH HHSNIGMS NIH HHS558-566https://www.ebi.ac.uk/biostudies/studies/S-EPMC8084946biostudies-literatureUnknown17(5)G-protein-coupled receptor-regulated cAMP production from endosomes can specify signaling to the nucleus by moving the source of cAMP without changing its overall amount. How this is possible remains unknown because cAMP gradients dissipate over the nanoscale, whereas endosomes typically localize micrometers from the nucleus. We show that the key location-dependent step for endosome-encoded transcriptional control is nuclear entry of cAMP-dependent protein kinase (PKA) catalytic subunits. These are sourced from punctate accumulations of PKA holoenzyme that are densely distributed in the cytoplasm and titrated by global cAMP into a discrete metastable state, in which catalytic subunits are bound but dynamically exchange. Mobile endosomes containing activated receptors collide with the metastable PKA puncta and pause in close contact. We propose that these properties enable cytoplasmic PKA to act collectively like a semiconductor, converting nanoscale cAMP gradients generated from endosomes into microscale elevations of free catalytic subunits to direct downstream signaling.Nature chemical biologySpatial decoding of endosomal cAMP signals by a metastable cytoplasmic PKA network.PMC8084946U54 CA224081U01 NS103522HL129689R01 DA010711R21 EB022798S10 OD017993R01 GM131641R37 DA010711R01 CA23130015PRE21770003EB022798MH120212R01 DA012864DA010711DA012864R01 MH120212F31 HL12968916PRE26420057R29 DA010711Pessino VPeng GEHuang Bvon Zastrow MfalseSpatial decoding of endosomal cAMP signals by a metastable cytoplasmic PKA network.G-protein-coupled receptor-regulated cAMP production from endosomes can specify signaling to the nucleus by moving the source of cAMP without changing its overall amount. How this is possible remains unknown because cAMP gradients dissipate over the nanoscale, whereas endosomes typically localize micrometers from the nucleus. We show that the key location-dependent step for endosome-encoded transcriptional control is nuclear entry of cAMP-dependent protein kinase (PKA) catalytic subunits. These are sourced from punctate accumulations of PKA holoenzyme that are densely distributed in the cytoplasm and titrated by global cAMP into a discrete metastable state, in which catalytic subunits are bound but dynamically exchange. Mobile endosomes containing activated receptors collide with the metastable PKA puncta and pause in close contact. We propose that these properties enable cytoplasmic PKA to act collectively like a semiconductor, converting nanoscale cAMP gradients generated from endosomes into microscale elevations of free catalytic subunits to direct downstream signaling.2021-01-01T00:00:00Z2021 May2024-02-15T13:18:56.083Z2022-02-11T10:00:20.011ZS-EPMC80849463364959810.1038/s41589-021-00747-0