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Increased Levels of cAMP by the Calcium-Dependent Activation of Soluble Adenylyl Cyclase in Parkin-Mutant Fibroblasts
Almost half of autosomal recessive early-onset parkinsonism has been associated with mutations in PARK2, coding for parkin, which plays an important role in mitochondria function and calcium homeostasis. Cyclic adenosine monophosphate (cAMP) is a major second messenger regulating mitochondrial metab...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468892/ https://www.ncbi.nlm.nih.gov/pubmed/30875974 http://dx.doi.org/10.3390/cells8030250 |
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author | Tanzarella, Paola Ferretta, Anna Barile, Simona Nicol Ancona, Mariella De Rasmo, Domenico Signorile, Anna Papa, Sergio Capitanio, Nazzareno Pacelli, Consiglia Cocco, Tiziana |
author_facet | Tanzarella, Paola Ferretta, Anna Barile, Simona Nicol Ancona, Mariella De Rasmo, Domenico Signorile, Anna Papa, Sergio Capitanio, Nazzareno Pacelli, Consiglia Cocco, Tiziana |
author_sort | Tanzarella, Paola |
collection | PubMed |
description | Almost half of autosomal recessive early-onset parkinsonism has been associated with mutations in PARK2, coding for parkin, which plays an important role in mitochondria function and calcium homeostasis. Cyclic adenosine monophosphate (cAMP) is a major second messenger regulating mitochondrial metabolism, and it is strictly interlocked with calcium homeostasis. Parkin-mutant (Pt) fibroblasts, exhibiting defective mitochondrial respiratory/OxPhos activity, showed a significant higher value of basal intracellular level of cAMP, as compared with normal fibroblasts (CTRL). Specific pharmacological inhibition/activation of members of the adenylyl cyclase- and of the phosphodiesterase-families, respectively, as well as quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis, indicate that the higher level of cAMP observed in Pt fibroblasts can contribute to a higher level of activity/expression by soluble adenylyl cyclase (sAC) and to low activity/expression of the phosphodiesterase isoform 4 (PDE4). As Ca(2+) regulates sAC, we performed quantitative calcium-fluorimetric analysis, showing a higher level of Ca(2+) in the both cytosol and mitochondria of Pt fibroblasts as compared with CTRL. Most notably, inhibition of the mitochondrial Ca(2+) uniporter decreased, specifically the cAMP level in PD fibroblasts. All together, these findings support the occurrence of an altered mitochondrial Ca(2+)-mediated cAMP homeostasis in fibroblasts with the parkin mutation. |
format | Online Article Text |
id | pubmed-6468892 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-64688922019-04-23 Increased Levels of cAMP by the Calcium-Dependent Activation of Soluble Adenylyl Cyclase in Parkin-Mutant Fibroblasts Tanzarella, Paola Ferretta, Anna Barile, Simona Nicol Ancona, Mariella De Rasmo, Domenico Signorile, Anna Papa, Sergio Capitanio, Nazzareno Pacelli, Consiglia Cocco, Tiziana Cells Article Almost half of autosomal recessive early-onset parkinsonism has been associated with mutations in PARK2, coding for parkin, which plays an important role in mitochondria function and calcium homeostasis. Cyclic adenosine monophosphate (cAMP) is a major second messenger regulating mitochondrial metabolism, and it is strictly interlocked with calcium homeostasis. Parkin-mutant (Pt) fibroblasts, exhibiting defective mitochondrial respiratory/OxPhos activity, showed a significant higher value of basal intracellular level of cAMP, as compared with normal fibroblasts (CTRL). Specific pharmacological inhibition/activation of members of the adenylyl cyclase- and of the phosphodiesterase-families, respectively, as well as quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis, indicate that the higher level of cAMP observed in Pt fibroblasts can contribute to a higher level of activity/expression by soluble adenylyl cyclase (sAC) and to low activity/expression of the phosphodiesterase isoform 4 (PDE4). As Ca(2+) regulates sAC, we performed quantitative calcium-fluorimetric analysis, showing a higher level of Ca(2+) in the both cytosol and mitochondria of Pt fibroblasts as compared with CTRL. Most notably, inhibition of the mitochondrial Ca(2+) uniporter decreased, specifically the cAMP level in PD fibroblasts. All together, these findings support the occurrence of an altered mitochondrial Ca(2+)-mediated cAMP homeostasis in fibroblasts with the parkin mutation. MDPI 2019-03-15 /pmc/articles/PMC6468892/ /pubmed/30875974 http://dx.doi.org/10.3390/cells8030250 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Tanzarella, Paola Ferretta, Anna Barile, Simona Nicol Ancona, Mariella De Rasmo, Domenico Signorile, Anna Papa, Sergio Capitanio, Nazzareno Pacelli, Consiglia Cocco, Tiziana Increased Levels of cAMP by the Calcium-Dependent Activation of Soluble Adenylyl Cyclase in Parkin-Mutant Fibroblasts |
title | Increased Levels of cAMP by the Calcium-Dependent Activation of Soluble Adenylyl Cyclase in Parkin-Mutant Fibroblasts |
title_full | Increased Levels of cAMP by the Calcium-Dependent Activation of Soluble Adenylyl Cyclase in Parkin-Mutant Fibroblasts |
title_fullStr | Increased Levels of cAMP by the Calcium-Dependent Activation of Soluble Adenylyl Cyclase in Parkin-Mutant Fibroblasts |
title_full_unstemmed | Increased Levels of cAMP by the Calcium-Dependent Activation of Soluble Adenylyl Cyclase in Parkin-Mutant Fibroblasts |
title_short | Increased Levels of cAMP by the Calcium-Dependent Activation of Soluble Adenylyl Cyclase in Parkin-Mutant Fibroblasts |
title_sort | increased levels of camp by the calcium-dependent activation of soluble adenylyl cyclase in parkin-mutant fibroblasts |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468892/ https://www.ncbi.nlm.nih.gov/pubmed/30875974 http://dx.doi.org/10.3390/cells8030250 |
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