دورية أكاديمية
Phosphatases control PKA-dependent functional microdomains at the outer mitochondrial membrane
| العنوان: | Phosphatases control PKA-dependent functional microdomains at the outer mitochondrial membrane |
|---|---|
| المؤلفون: | Burdyga, A, Surdo, N, Monterisi, S, Di Benedetto, G, Grisan, F, Penna, E, Pellegrini, L, Bortolozzi, M, Swietach, P, Pozzan, T, Lefkimmiatis, K |
| بيانات النشر: | National Academy of Sciences |
| سنة النشر: | 2018 |
| المجموعة: | Oxford University Research Archive (ORA) |
| الوصف: | Evidence supporting the heterogeneity in cAMP and PKA signaling is rapidly accumulating and has been largely attributed to the localization or activity of adenylate cyclases, phosphodiesterases, and A-kinase–anchoring proteins in different cellular subcompartments. However, little attention has been paid to the possibility that, despite homogeneous cAMP levels, a major heterogeneity in cAMP/PKA signaling could be generated by the spatial distribution of the final terminators of this cascade, i.e., the phosphatases. Using FRET-based sensors to monitor cAMP and PKA-dependent phosphorylation in the cytosol and outer mitochondrial membrane (OMM) of primary rat cardiomyocytes, we demonstrate that comparable cAMP increases in these two compartments evoke higher levels of PKA-dependent phosphorylation in the OMM. This difference is most evident for small, physiological increases of cAMP levels and with both OMM-located probes and endogenous OMM proteins. We demonstrate that this disparity depends on differences in the rates of phosphatase-dependent dephosphorylation of PKA targets in the two compartments. Furthermore, we show that the activity of soluble phosphatases attenuates PKA-driven activation of the cAMP response element-binding protein while concurrently enhancing PKA-dependent mitochondrial elongation. We conclude that phosphatases can sculpt functionally distinct cAMP/PKA domains even in the absence of gradients or microdomains of this messenger. We present a model that accounts for these unexpected results in which the degree of PKA-dependent phosphorylation is dictated by both the subcellular distribution of the phosphatases and the different accessibility of membrane-bound and soluble phosphorylated substrates to the cytosolic enzymes. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://ora.ox.ac.uk/objects/uuid:18804f1a-9bc1-443b-b751-a8b4619cdbc2Test; https://doi.org/10.1073/pnas.1806318115Test |
| DOI: | 10.1073/pnas.1806318115 |
| الإتاحة: | https://doi.org/10.1073/pnas.1806318115Test https://ora.ox.ac.uk/objects/uuid:18804f1a-9bc1-443b-b751-a8b4619cdbc2Test |
| حقوق: | info:eu-repo/semantics/openAccess ; CC Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) |
| رقم الانضمام: | edsbas.AEEC56CD |
| قاعدة البيانات: | BASE |
| DOI: | 10.1073/pnas.1806318115 |
|---|