Bicarbonate-responsive “soluble” adenylyl cyclase defines a nuclear cAMP microdomain

Zippin, Jonathan H.; Farrell, Jeanne; Huron, David R; Kamenetsky, Margarita; Hess, Kenneth C.; Fischman, Donald A.; Levin, Lonny R.; Buck, Jochen

doi:10.1083/jcb.200311119

Cited by 161 publications

(183 citation statements)

References 37 publications

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“…We also used our antibody to examine sAC localization in PC12 cells. We and others previously demonstrated sAC to be localized to the cytoplasm, as well as the mitochondria, centrosomes, and nuclei in multiple cell lines and tissues (22,24,36). In PC12 cells, we observed predominantly cytoplasmic staining, with the strongest intensity around the periphery (Fig.…”

Section: Ngf Signals Via Calcium To Raise Intracellular Camp and Actimentioning

confidence: 70%

“…Among mammalian adenylyl cyclases, sAC is uniquely bicarbonate-stimulated (19,21,36,37), and cAMP production via sAC represents the only known signaling effect initiated by bicarbonate (24). Generation of cAMP can lead to activation of Rap1 (5, 11, 38, 39), and we tested whether bicarbonate could stimulate Rap1 activation in PC12 cells.…”

Section: Ngf Signals Via Calcium To Raise Intracellular Camp and Actimentioning

confidence: 99%

“…In contrast to tmACs, sAC is not regulated by heterotrimeric G proteins but is, instead, regulated by bicarbonate (19) and calcium (20,21) ions. Also, in contrast to tmACs, sAC is not bound to the plasma membrane but is localized to various intracellular compartments (22), where it is thought to be the source of local pools of cAMP (23,24). In sperm, bicarbonate regulation of sAC mediates a number of maturation events essential for fertilization (25,26).…”

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confidence: 99%

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Soluble Adenylyl Cyclase Mediates Nerve Growth Factor-induced Activation of Rap1

Stessin

Zippin

Kamenetsky³

et al. 2006

Journal of Biological Chemistry

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Nerve growth factor (NGF) and the ubiquitous second messenger cyclic AMP (cAMP) are both implicated in neuronal differentiation. Multiple studies indicate that NGF signals to at least a subset of its targets via cAMP, but the link between NGF and cAMP has remained elusive. Here, we have described the use of small molecule inhibitors to differentiate between the two known sources of cAMP in mammalian cells, bicarbonate-and calcium-responsive soluble adenylyl cyclase (sAC) and G protein-regulated transmembrane adenylyl cyclases. These inhibitors, along with sAC-specific small interfering RNA, reveal that sAC is uniquely responsible for the NGF-elicited rise in cAMP and is essential for the NGF-induced activation of the small G protein Rap1 in PC12 cells. In contrast and as expected, transmembrane adenylyl cyclase-generated cAMP is responsible for Rap1 activation by the G protein-coupled receptor ligand PACAP (pituitary adenylyl cyclase-activating peptide). These results identify sAC as a mediator of NGF signaling and reveal the existence of distinct pathways leading to cAMP-dependent signal transduction.

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Section: Ngf Signals Via Calcium To Raise Intracellular Camp and Actimentioning

confidence: 70%

Section: Ngf Signals Via Calcium To Raise Intracellular Camp and Actimentioning

confidence: 99%

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confidence: 99%

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Soluble Adenylyl Cyclase Mediates Nerve Growth Factor-induced Activation of Rap1

Stessin

Zippin

Kamenetsky³

et al. 2006

Journal of Biological Chemistry

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“…unknown. More recently, AKAP distribution throughout cells (52) and the observation that sAC and cAMP effector proteins reside inside the nucleus and in mitochondria (8,10,12,53) have highlighted the importance of cyclic nucleotides inside cellular organelles. Our finding that a specific PDE isoform, PDE2A2, co-localizes with these proteins in the mitochondrial matrix now confirms that a complete cAMP signaling system exists in this cellular subcompartment.…”

Section: Discussionmentioning

confidence: 99%

A Phosphodiesterase 2A Isoform Localized to Mitochondria Regulates Respiration

Acı́n-Pérez

Russwurm

Günnewig

et al. 2011

Journal of Biological Chemistry

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120

133

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Mitochondria are central organelles in cellular energy metabolism, apoptosis, and aging processes. A signaling network regulating these functions was recently shown to include soluble adenylyl cyclase as a local source of the second messenger cAMP in the mitochondrial matrix. However, a mitochondrial cAMPdegrading phosphodiesterase (PDE) necessary for switching off this cAMP signal has not yet been identified. Here, we describe the identification and characterization of a PDE2A isoform in mitochondria from rodent liver and brain. We find that mitochondrial PDE2A is located in the matrix and that the unique N terminus of PDE2A isoform 2 specifically leads to mitochondrial localization of this isoform. Functional assays show that mitochondrial PDE2A forms a local signaling system with soluble adenylyl cyclase in the matrix, which regulates the activity of the respiratory chain. Our findings complete a cAMP signaling cascade in mitochondria and have implications for understanding the regulation of mitochondrial processes and for their pharmacological modulation.Mitochondria play central roles in cellular energy metabolism, as well as in the regulation of cell cycle progression, apoptosis, and aging processes (1, 2). Despite their importance, signaling into, from, and within mitochondria is still not well understood. Emerging signaling mechanisms in mitochondria and between the organelle and its environment include reversible protein deacetylation (3, 4), redox regulation and reactive oxygen species formation (5-7), and cyclic adenosine monophosphate (cAMP) signaling (8, 9).cAMP-dependent effects and proteins of cAMP signaling systems, such as cAMP-responsive element-binding protein (CREB), protein kinase A (PKA), and A-kinase anchoring proteins (AKAPs), 3 have been described in mitochondria (10 -12). In addition to these effector proteins, a complete cAMP signaling microdomain requires enzymes for synthesis and degradation of the second messenger. Although an intramitochondrial cAMP source has been identified recently (8), there is no known cAMP-degrading enzyme in this organelle. Cyclic AMP is formed inside mitochondria by soluble adenylyl cyclase (sAC) (8), a member of Class III of the nucleotidyl cyclase family, which also comprises the G-protein-regulated transmembrane adenylyl cyclases (13). Unique from transmembrane adenylyl cyclases, sAC is activated by bicarbonate (14), and it appears to act as a metabolic sensor (15), whose mitochondrial form(s) seems to modulate PKA-mediated regulation of respiration (8) and apoptosis (16).The opponents of the cyclic nucleotide-forming cyclases are cyclic nucleotide monophosphate (cNMP)-degrading phosphodiesterases (PDEs). Mammalian cells contain a varying subset of members of the classical PDE family, which comprises 11 PDE gene families (PDE1-11) (17, 18) and non-generic PDEs such as the protein human Prune (19,20). The isoforms of the generic PDEs comprise homologous catalytic domains, fused to varying regulatory domains, making them sensitive to a variety of signals s...

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“…After its cloning [36], mammalian sAC has been found in different cell compartments such as the nucleus [37][38][39], mitochondria and in membrane microdomains, such as caveolae, and lipid rafts, which are also known as the low density-detergent insoluble membrane fraction (LD-DIM) (reviewed in [40]). It is now known that in both nuclei and mitochondria the main source of cAMP synthesis is from sAC.…”

Section: Susac Association With Micro Domainsmentioning

confidence: 99%