Spatial decoding of endosomal cAMP signals by a metastable cytoplasmic PKA network.
Nat Chem Biol
; 17(5): 558-566, 2021 05.
Article
em En
| MEDLINE
| ID: mdl-33649598
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Endossomos
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Transdução de Sinais
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Receptores Adrenérgicos beta 2
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Proteínas Quinases Dependentes de AMP Cíclico
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AMP Cíclico
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Citoplasma
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article