Calcium-sensing soluble adenylyl cyclase mediates TNF signal transduction in human neutrophils

Han, Hee‐Sun; Stessin, A.; Roberts, Julia; Hess, Kenneth C.; Gautam, Narinder; Kamenetsky, Margarita; Lou, Olivia; Hyde, Edward; Nathan, Noah; Müller, William A.; Buck, Jochen; Levin, Lonny R.; Nathan, Carl

doi:10.1084/jem.20050778

Cited by 61 publications

(79 citation statements)

References 38 publications

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“…Interestingly, it has been suggested that Trk and p75 NTR may act either as subunits of a single receptor complex or as independent transducers of distinct neurotrophin functions (Chao, 1994). Although it is generally thought that the NGF-induced activation of Rap1, which we have shown to be mediated via sAC (Stessin et al, 2006), involves TrkA, rather than p75 NTR , we have also found sAC to mediate the activation of Rap1 by TNF in neutrophils (Han et al, 2005). Thus, the roles of TrkA and p75 NTR in the activation of sAC by NGF are a subject for future studies.…”

Section: As Revealed Incontrasting

confidence: 51%

“Soluble” adenylyl cyclase‐generated cyclic adenosine monophosphate promotes fast migration in PC12 cells

Young

Mehdi

Stohl

et al. 2007

J of Neuroscience Research

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In a model for neuronal movement, PC12 cells undergo fast migration in response to nerve growth factor (NGF) and phorbol ester (PMA). We previously showed that NGF increases intracellular cAMP via activation of soluble adenylyl cyclase (sAC). In this report, we demonstrate that sAC activation is an essential component of NGF-+PMA-induced fast migration in PC12 cells. Interestingly, PMA also raises intracellular cAMP but does so by stimulating transmembrane adenylyl cyclases (tmAC); however, this tmAC-generated cAMP does not contribute to fast migration. Therefore, cells must possess independent pools of cAMP capable of modulating distinct functions.Keywords adenylyl cyclase; nerve growth factor; neuron; compartmentalization; protein kinase C Neuronal migration and differentiation constitute key processes in the development of the central nervous system. The rat pheochromocytoma cell line PC12 has been extensively used as a model for the morphological changes that accompany both processes. When treated with nerve growth factor (NGF) for long periods (48-72 hr), PC12 cells extend neurites in a process analogous to differentiation of sympathetic neurons (Levi-Montalcini and Angeletti, 1968;Greene and Tischler, 1982;Vaudry et al., 2002). Conversely, when PC12 cells, plated on laminin-coated surfaces, are simultaneously stimulated with NGF and phorbol 12-myristate-13-acetate (PMA), the cell body recedes away from points of attachment to the plate surface, and the cells assume a crescent shape (Glowacka and Wagner, 1990). The latter phenomenon is rapid (observable within 1 hr of NGF + PMA addition) and has been considered a model for "fast neuronal migration."The signaling cascades that mediate the fast migration process have not been adequately described. Specifically, it is known that PMA exerts its effects via the activation of protein kinase C (PKC), which was independently shown to be essential for cell motility in primary (Choe et al., 2003). NGF has been shown to promote the survival and differentiation of multiple neuronal populations within the central nervous system (LeviMontalcini and Angeletti, 1968), but the signaling mechanisms involved in NGF-induced neuritogenesis remain controversial (Vaudry et al., 2002).We recently identified "soluble" adenylyl cyclase (sAC) as the source of cAMP downstream of NGF and a mediator of NGF-induced activation of the monomeric GTPase Rap1 in PC12 cells (Stessin et al., 2006). sAC is a ubiquitously expressed cAMP source in mammalian cells, distinct from the classically described trans-membrane adenylyl cyclases (tmACs) in its subcellular localization and biochemical profile. In this report, we demonstrate that the NGFsAC signaling axis is also required for fast migration. We also show that stimulation of PC12 cells with PMA results in cAMP elevation via tmACs, but, unlike sAC-generated cAMP, tmAC-generated cAMP does not contribute to the fast migration phenomenon. These results reveal the existence of distinct pools of cAMP, which are generated by independent sour...

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Section: As Revealed Incontrasting

confidence: 51%

“Soluble” adenylyl cyclase‐generated cyclic adenosine monophosphate promotes fast migration in PC12 cells

Young

Mehdi

Stohl

et al. 2007

J of Neuroscience Research

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“…To examine the role of sAC in EC apoptosis, treatment with the selective sAC inhibitor KH7 (10 mol/liter) was performed (15). Previous studies demonstrated that KH7 at a similar range of concentrations inhibits sAC in various cell types (15,18). In our model, KH7 applied at concentrations of 1-100 mol/liter revealed a marked anti-apoptotic effect and no necrotic effect at 10 mol/liter (data not shown).…”

Section: Sac Is Involved In Simulated Ischemia-or Acidosis-inducedmentioning

confidence: 76%

Soluble Adenylyl Cyclase Controls Mitochondria-dependent Apoptosis in Coronary Endothelial Cells

Kumar

Kostin

Flacke

et al. 2009

Journal of Biological Chemistry

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The cAMP signaling pathway plays an essential role in modulating the apoptotic response to various stress stimuli. Until now, it was attributed exclusively to the activity of the G-protein-responsive transmembrane adenylyl cyclase. In addition to transmembrane AC, mammalian cells possess a second source of cAMP, the ubiquitously expressed soluble adenylyl cyclase (sAC). However, the role of this cyclase in apoptosis was unknown. A mitochondrial localization of this cyclase has recently been demonstrated, which led us to the hypothesis that sAC may play a role in apoptosis through modulation of mitochondria-dependent apoptosis. To prove this hypothesis, apoptosis was induced by simulated in vitro ischemia or by acidosis, which is an important component of ischemia. Suppression of sAC activity with the selective inhibitor KH7 or sAC knockdown by small interfering RNA transfection abolished endothelial apoptosis. Furthermore, pharmacological inhibition or knockdown of protein kinase A, an important cAMP target, demonstrated a significant anti-apoptotic effect. Analysis of the underlying mechanisms revealed (i) the translocation of sAC to mitochondria under acidic stress and (ii) activation of the mitochondrial pathway of apoptosis, i.e. cytochrome c release and caspase-9 cleavage. sAC inhibition or knockdown abolished the activation of the mitochondrial pathway of apoptosis. Analysis of mitochondrial co-localization of Bcl-2 family proteins demonstrated sAC-and protein kinase A-dependent translocation of Bax to mitochondria. Taken together, these results suggest the important role of sAC in modulating the mitochondria-dependent pathway of apoptosis in endothelial cells. Increasing evidence suggests that apoptosis of endothelial cells (EC)3 may be responsible for acute and chronic vascular diseases, e.g. through atherogenesis (1), endothelial dysfunction (2), or thrombosis (3). Within several signaling mechanisms, a cAMP-dependent signaling pathway plays a substantial role in mediating apoptotic cell death induced by various stress factors. Elevation of the cellular cAMP either by forskolin-induced stimulation of the G-protein-responsive transmembrane adenylyl cyclase (tmAC) or by treatment with cAMP analogs has been shown to lead to both induction and suppression of apoptosis in different cell types (4 -7). This discrepancy may be due to differences in cell types and experimental models. Alternatively, a lack of specificity of tmAC-induced signals, especially directed to distant intracellular targets like mitochondria, may be a cause of the discrepancy. Indeed, the classical model of cAMP signaling requires the diffusion of cAMP from plasma membrane-localized tmAC to targets localized throughout the cell. Diffusion of cAMP throughout the cytosol makes it difficult to selectively activate distally localized targets without also activating more proximal targets. Therefore, such diffusion of cAMP would likely diminish specificity, selectivity, and signal strength. This model is further complicated by the presence of p...

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“…Previously, calcium had been identified as an activator of sAC (20,21,28,41). On the other hand, calcium is also known to regulate several types of tmACs, some of which are expressed in PC12 cells (31).…”

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

confidence: 99%

“…In sperm, bicarbonate regulation of sAC mediates a number of maturation events essential for fertilization (25,26). In somatic tissues, bicarbonate regulation of sAC in epididymis permits clear cells to respond to luminal pH (27), and calcium regulation of sAC in neutrophils is essential for the tumor necrosis factorinduced respiratory burst (28). Tumor necrosis factor-induced respiratory burst has been proposed to occur via Rap1, and tumor necrosis factor activation of Rap1 in neutrophils appears to be mediated by sAC (28).…”

mentioning

confidence: 99%

“…In somatic tissues, bicarbonate regulation of sAC in epididymis permits clear cells to respond to luminal pH (27), and calcium regulation of sAC in neutrophils is essential for the tumor necrosis factorinduced respiratory burst (28). Tumor necrosis factor-induced respiratory burst has been proposed to occur via Rap1, and tumor necrosis factor activation of Rap1 in neutrophils appears to be mediated by sAC (28). We explored whether sAC might represent the source of cAMP leading to the activation of Rap1 in other contexts unexplained by heterotrimeric G protein activation of tmACs.…”

mentioning

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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Calcium-sensing soluble adenylyl cyclase mediates TNF signal transduction in human neutrophils

Cited by 61 publications

References 38 publications

“Soluble” adenylyl cyclase‐generated cyclic adenosine monophosphate promotes fast migration in PC12 cells

“Soluble” adenylyl cyclase‐generated cyclic adenosine monophosphate promotes fast migration in PC12 cells

Soluble Adenylyl Cyclase Controls Mitochondria-dependent Apoptosis in Coronary Endothelial Cells

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

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