Neurotrophin induced cAMP and IP<sub>3</sub> responses in PC12 cells

Knipper, Marlies; Beck, A.; Rylett, Jane; Breer, Heinz

doi:10.1016/0014-5793(93)81382-a

Cited by 48 publications

(32 citation statements)

References 34 publications

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“…Second, NGF is shown for the first time to signal directly through the second messenger cAMP via adenylyl cyclase activation. It was previously reported that NGF can elevate cAMP levels within 1 s in the membranes of PC12 cells (6). These investigators proposed cross-talk between the low affinity neurotrophin receptor p75 NTR and a G protein-mediated cascade.…”

Section: Discussionmentioning

confidence: 94%

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: Discussionmentioning

confidence: 94%

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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“…In PC12 cells deficient in PKA, treatment with NGF increased the levels of both mRNA and saxitoxin binding for type II sodium channels; however, recordings showed no detectable I Na in these cells, indicating that PKA was critical in the expression of functional channels (Ginty et al 1992). Although early studies demonstrated that NGF rapidly increased intracellular levels of cyclic AMP (Higuchi et al 2003;Knipper et al 1993), establishing a causal link has been elusive. Recent studies in PC12 cells showed that NGF elevated cyclic AMP levels through activation of soluble rather than transmembrane adenylyl cyclase and that this cyclic AMP increased the activity of the small G protein, Rap1 (Stressin et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Augmented Sodium Currents Contribute to the Enhanced Excitability of Small Diameter Capsaicin-Sensitive Sensory Neurons Isolated From Nf1+/− Mice

Wang¹,

Duan²,

Hingtgen

et al. 2010

Journal of Neurophysiology

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Wang Y, Duan JH, Hingtgen CM, Nicol GD. Augmented sodium currents contribute to the enhanced excitability of small diameter capsaicin-sensitive sensory neurons isolated from Nf1ϩ/Ϫ mice. J Neurophysiol 103: 2085-2094, 2010. First published February 17, 2010 doi:10.1152/jn.01010.2009. Neurofibromin, the product of the Nf1 gene, is a guanosine triphosphatase activating protein (GAP) for p21ras (Ras) that accelerates conversion of active Ras-GTP to inactive Ras-GDP. Sensory neurons with reduced levels of neurofibromin likely have augmented Ras-GTP activity. We reported previously that sensory neurons isolated from a mouse model with a heterozygous mutation of the Nf1 gene (Nf1ϩ/Ϫ) exhibited greater excitability compared with wild-type mice. To determine the mechanism giving rise to the augmented excitability, differences in specific membrane currents were examined. Consistent with the enhanced excitability of Nf1ϩ/Ϫ neurons, peak current densities of both tetrodotoxin-resistant sodium current (TTX-R I Na ) and TTX-sensitive (TTX-S) I Na were significantly larger in Nf1ϩ/Ϫ than in wild-type neurons. Although the voltages for half-maximal activation (V 0.5 ) were not different, there was a significant depolarizing shift in the V 0.5 for steady-state inactivation of both TTX-R and TTX-S I Na in Nf1ϩ/Ϫ neurons. In addition, levels of persistent I Na were significantly larger in Nf1ϩ/Ϫ neurons. Neither delayed rectifier nor A-type potassium currents were altered in Nf1ϩ/Ϫ neurons. These results demonstrate that enhanced production of action potentials in Nf1ϩ/Ϫ neurons results, in part, from larger current densities and a depolarized voltage dependence of steady-state inactivation for I Na that potentially leads to a greater availability of sodium channels at voltages near the firing threshold for the action potential.

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“…Melanoma cells contain nerve growth factor (23) and high affinity nerve growth factor receptor, Trk A, is expressed in small and medium diameter DRG neurons (24), which also express ET A receptor (18). Nerve growth factor elevates cAMP (25) and cAMP up-regulates ET A -receptor mRNA (26). Thus, nerve growth factor might be a cause of the increase in ET A -receptor mRNA in the DRG of melanoma-bearing mice.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Endothelin and ETA Endothelin Receptor in Mechanical Allodynia in Mice Given Orthotopic Melanoma Inoculation

et al. 2008

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Abstract. We investigated whether endothelin (ET) would be involved in skin cancer pain in mice. Orthotopic inoculation of B16-BL6 melanoma cells into the plantar region of the hind paw produced marked mechanical allodynia in C57BL/ 6 mice. Intraplantar injections of the ET Areceptor antagonist BQ-123 (0.3 -3 nmol/ site), but not the ET B -receptor antagonist BQ-788 (1 and 3 nmol/ site), inhibited mechanical allodynia in mice with grown melanoma. In naive mice, an intraplantar injection of tumor extract (1 and 3 mg/ site), which was prepared from the grown melanoma in the paw, produced mechanical allodynia, which was inhibited by BQ-123 and BQ-788 at doses of 3 and 10 nmol/ site. An intraplantar injection of ET-1 (1 and 10 pmol/ site) elicited licking behavior, which was increased in the melanoma-bearing hind paw. BQ-123 (3 and 10 nmol/ site) inhibited licking induced by ET-1 (10 pmol/ site). The level of mRNA of ET A , but not ET B , receptor, was significantly increased in the dorsal root ganglia on the inoculated side. Cultured B16-BL6 cells contained ET, and the melanoma mass increased the concentration of ET as it grew bigger. These results suggest that ET-1 and ET A receptor are at least partly involved in the induction of pain induced by melanoma cell inoculation.

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Neurotrophin induced cAMP and IP₃ responses in PC12 cells

Cited by 48 publications

References 34 publications

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

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

Augmented Sodium Currents Contribute to the Enhanced Excitability of Small Diameter Capsaicin-Sensitive Sensory Neurons Isolated From Nf1+/− Mice

Involvement of Endothelin and ETA Endothelin Receptor in Mechanical Allodynia in Mice Given Orthotopic Melanoma Inoculation

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Neurotrophin induced cAMP and IP3 responses in PC12 cells

Cited by 48 publications

References 34 publications

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

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

Augmented Sodium Currents Contribute to the Enhanced Excitability of Small Diameter Capsaicin-Sensitive Sensory Neurons Isolated From Nf1+/− Mice

Involvement of Endothelin and ETA Endothelin Receptor in Mechanical Allodynia in Mice Given Orthotopic Melanoma Inoculation

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Neurotrophin induced cAMP and IP₃ responses in PC12 cells