Sensory Signaling Pathways in Inflammatory and Neuropathic Pain

2019 ◽  
pp. 608-658 ◽  
Author(s):  
Hanneke L. D. M. Willemen ◽  
Niels Eijkelkamp
Keyword(s):  
Neuropathic Pain ◽  
Sensory Neuron ◽  
Intracellular Signaling ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Signaling Cascades ◽  
Mitogen Activated Protein ◽  
Ligand Interactions ◽  
Intracellular Signal ◽  
Neuron Function

Sensory neuron sensitivity is modulated by a large variety of mediators that can activate a plethora of signaling cascades. These signaling cascades allow sensory neurons to show remarkable plasticity in response to injury and inflammation. The understanding of intracellular signaling mechanisms that regulate sensory neuron function downstream of receptor–ligand interactions or electrical activity is still at a relatively developing stage. This article highlights what is known about some of the components of classical intracellular signal transduction cascades, such as cyclic adenosine monophosphate (cAMP) and downstream cAMP sensors, mitogen-activated protein kinases, and others in regulating sensory neuron function. How these transduction cascades may contribute to the initiation, maintenance, or even resolution of inflammatory and neuropathic pain is discussed. Moreover, the focus is on how intracellular signaling cascades themselves are subject to plasticity and how this plasticity may underlie the development of chronic pain.

scholarly journals Integration of Rap1 and Calcium Signaling

2020 ◽  
Vol 21 (5) ◽  
pp. 1616 ◽  
Author(s):  
Ramoji Kosuru ◽  
Magdalena Chrzanowska
Keyword(s):  
Intracellular Signaling ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Nucleotide Exchange ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Cardiac Excitation

Ca2+ is a universal intracellular signal. The modulation of cytoplasmic Ca2+ concentration regulates a plethora of cellular processes, such as: synaptic plasticity, neuronal survival, chemotaxis of immune cells, platelet aggregation, vasodilation, and cardiac excitation–contraction coupling. Rap1 GTPases are ubiquitously expressed binary switches that alternate between active and inactive states and are regulated by diverse families of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Active Rap1 couples extracellular stimulation with intracellular signaling through secondary messengers—cyclic adenosine monophosphate (cAMP), Ca2+, and diacylglycerol (DAG). Much evidence indicates that Rap1 signaling intersects with Ca2+ signaling pathways to control the important cellular functions of platelet activation or neuronal plasticity. Rap1 acts as an effector of Ca2+ signaling when activated by mechanisms involving Ca2+ and DAG-activated (CalDAG-) GEFs. Conversely, activated by other GEFs, such as cAMP-dependent GEF Epac, Rap1 controls cytoplasmic Ca2+ levels. It does so by regulating the activity of Ca2+ signaling proteins such as sarcoendoplasmic reticulum Ca2+-ATPase (SERCA). In this review, we focus on the physiological significance of the links between Rap1 and Ca2+ signaling and emphasize the molecular interactions that may offer new targets for the therapy of Alzheimer’s disease, hypertension, and atherosclerosis, among other diseases.

scholarly journals Cyclic AMP response element-binding protein is required in excitatory neurons in the forebrain to sustain wakefulness

SLEEP ◽  
2020 ◽  
Author(s):  
Mathieu E Wimmer ◽  
Rosa Cui ◽  
Jennifer M Blackwell ◽  
Ted Abel
Keyword(s):  
Cyclic Amp ◽  
Intracellular Signaling ◽  
Target Genes ◽  
Binding Protein ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Response Element ◽  
Creb Phosphorylation ◽  
Element Binding Protein ◽  
And Control

Abstract The molecular and intracellular signaling processes that control sleep and wake states remain largely unknown. A consistent observation is that the cyclic adenosine monophosphate (AMP) response element-binding protein (CREB), an activity-dependent transcription factor, is differentially activated during sleep and wakefulness. CREB is phosphorylated by the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway as well as other kinases, and phosphorylated CREB promotes the transcription of target genes. Genetic studies in flies and mice suggest that CREB signaling influences sleep/wake states by promoting and stabilizing wakefulness. However, it remains unclear where in the brain CREB is required to drive wakefulness. In rats, CREB phosphorylation increases in the cerebral cortex during wakefulness and decreases during sleep, but it is not known if this change is functionally relevant to the maintenance of wakefulness. Here, we used the Cre/lox system to conditionally delete CREB in the forebrain (FB) and in the locus coeruleus (LC), two regions known to be important for the production of arousal and wakefulness. We used polysomnography to measure sleep/wake levels and sleep architecture in conditional CREB mutant mice and control littermates. We found that FB-specific deletion of CREB decreased wakefulness and increased non-rapid eye movement sleep. Mice lacking CREB in the FB were unable to sustain normal periods of wakefulness. On the other hand, deletion of CREB from LC neurons did not change sleep/wake levels or sleep/wake architecture. Taken together, these results suggest that CREB is required in neurons within the FB but not in the LC to promote and stabilize wakefulness.

scholarly journals Mel1c Mediated Monochromatic Light-Stimulated IGF-I Synthesis through the Intracellular Gαq/PKC/ERK Signaling Pathway

2019 ◽  
Vol 20 (7) ◽  
pp. 1682
Author(s):  
Shujie Ning ◽  
Zixu Wang ◽  
Jing Cao ◽  
Yulan Dong ◽  
Yaoxing Chen
Keyword(s):  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Monochromatic Light ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Erk Signaling ◽  
Sham Operation ◽  
Intracellular Signaling Pathway ◽  
Igf I

Previous studies have demonstrated that monochromatic light affects plasma melatonin (MEL) levels, which in turn regulates hepatic insulin-like growth factor I (IGF-I) secretion via the Mel1c receptor. However, the intracellular signaling pathway initiated by Mel1c remains unclear. In this study, newly hatched broilers, including intact, sham operation, and pinealectomy groups, were exposed to either white (WL), red (RL), green (GL), or blue (BL) light for 14 days. Experiments in vivo showed that GL significantly promoted plasma MEL formation, which was accompanied by an increase in the MEL receptor, Mel1c, as well as phosphorylated extracellular regulated protein kinases (p-ERK1/2), and IGF-I expression in the liver, compared to the other light-treated groups. In contrast, this GL stimulation was attenuated by pinealectomy. Exogenous MEL elevated the hepatocellular IGF-I level, which is consistent with increases in cyclic adenosine monophosphate (cAMP), Gαq, phosphorylated protein kinase C (p-PKC), and p-ERK1/2 expression. However, the Mel1c selective antagonist prazosin suppressed the MEL-induced expression of IGF-I, Gαq, p-PKC, and p-ERK1/2, while the cAMP concentration was barely affected. In addition, pretreatment with Ym254890 (a Gαq inhibitor), Go9863 (a PKC inhibitor), and PD98059 (an ERK1/2 inhibitor) markedly attenuated MEL-stimulated IGF-I expression and p-ERK1/2 activity. These results indicate that Mel1c mediates monochromatic GL-stimulated IGF-I synthesis through intracellular Gαq/PKC/ERK signaling.

Investigation of distinct molecular pathways in migraine induction using calcitonin gene-related peptide and sildenafil

Cephalalgia ◽  
2019 ◽  
Vol 39 (14) ◽  
pp. 1776-1788 ◽  
Author(s):  
Samaira Younis ◽  
Casper E Christensen ◽  
Nikolaj M Toft ◽  
Thomas Søborg ◽  
Faisal M Amin ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Calcitonin Gene Related Peptide ◽  
Guanosine Monophosphate ◽  
Related Peptide ◽  
Intracellular Signaling Pathways ◽  
Calcitonin Gene

Objective Migraine displays clinical heterogeneity of attack features and attack triggers. The question is whether this heterogeneity is explained by distinct intracellular signaling pathways leading to attacks with distinct clinical features. One well-known migraine-inducing pathway is mediated by cyclic adenosine monophosphate and another by cyclic guanosine monophosphate. Calcitonin gene-related peptide triggers migraine via the cyclic adenosine monophosphate pathway and sildenafil via the cyclic guanosine monophosphate pathway. To date, no studies have examined whether migraine induction mediated via the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways yields similar attacks within the same patients. Methods Patients were subjected to migraine induction on two separate days using calcitonin gene-related peptide (1.5 µg/min for 20 minutes) and sildenafil (100 mg) in a double-blind, randomized, double-dummy, cross-over design. Data on headache intensity, characteristics and accompanying symptoms were collected until 24 hours after drug administration. Results Thirty-four patients were enrolled and 27 completed both study days. Seventeen patients developed migraine after both study drugs (63%; 95% CI: 42–81). Eight patients developed migraine on one day only (seven after sildenafil and one after calcitonin gene-related peptide). Two patients did not develop migraine on either day. Headache laterality, nausea, photophobia and phonophobia were similar between drugs in 77%, 65%, 100%, and 94%, respectively, of the 17 patients who developed attacks on both days. Conclusion A majority of patients developed migraine after both calcitonin gene-related peptide and sildenafil. This supports the hypothesis that the cyclic adenosine monophosphate and cyclic guanosine monophosphate intracellular signaling pathways in migraine induction converge in a common cellular determinator, which ultimately triggers the same attacks. Trial registration: ClinicalTrials.gov Identifier: NCT03143465.

scholarly journals Emerging themes of cAMP regulation of the pulmonary endothelial barrier

2011 ◽  
Vol 300 (5) ◽  
pp. L667-L678 ◽  
Author(s):  
Sarah L. Sayner
Keyword(s):  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Signaling Cascades ◽  
Camp Signaling ◽  
Endothelial Barrier ◽  
Adenylyl Cyclases ◽  
Cortical Actin ◽  
Membrane Compartment ◽  
Barrier Regulation ◽  
Actomyosin Contraction

The presence of excess fluid in the interstitium and air spaces of the lung presents severe restrictions to gas exchange. The pulmonary endothelial barrier regulates the flux of fluid and plasma proteins from the vascular space into the underlying tissue. The integrity of this endothelial barrier is dynamically regulated by transitions in cAMP (3′,5′-cyclic adenosine monophosphate), which are synthesized in discrete subcellular compartments. Cyclic AMP generated in the subplasma membrane compartment acts through PKA and Epac (exchange protein directly activated by cAMP) to tighten cell adhesions, strengthen cortical actin, reduce actomyosin contraction, and decrease permeability. Confining cAMP within the subplasma membrane space is critical to its barrier-protective properties. When cAMP escapes the near membrane compartment and gains access to the cytosolic compartment, or when soluble adenylyl cyclases generate cAMP within the cytosolic compartment, this second messenger activates established cytosolic cAMP signaling cascades to perturb the endothelial barrier through PKA-mediated disruption of microtubules. Thus the concept of cAMP compartmentalization in endothelial barrier regulation is gaining momentum and new possibilities are being unveiled for cytosolic cAMP signaling with the emergence of the bicarbonate-regulated mammalian soluble adenylyl cyclase (sAC or AC10).

Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2127-2134 ◽  
Author(s):  
Derek S. Sim ◽  
Glenn Merrill-Skoloff ◽  
Barbara C. Furie ◽  
Bruce Furie ◽  
Robert Flaumenhaft
Keyword(s):  
Vascular Injury ◽  
Intracellular Signaling ◽  
Thrombus Formation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
In Vivo Model ◽  
The Status ◽  
Platelet Accumulation ◽  
Camp Levels

Abstract Platelet accumulation at sites of vascular injury is the primary event in arterial thrombosis. Initial platelet accrual into thrombi is mediated by interactions of platelet adhesion receptors with ligands on the injured endothelium or in the sub-endothelial matrix. The role of intracellular signals in initial platelet accumulation at sites of endothelial injury, however, is the subject of debate. We have used a newly discovered inhibitor of phosphodiesterase 3A (PDE3A) and the well-characterized PDE3A inhibitor, cilostazol, to modulate 3′,5′-cyclic adenosine monophosphate (cAMP) levels in an in vivo model that enables the kinetic analysis of platelet accumulation. These studies demonstrate that elevation of basal cAMP levels results in an overall decline in platelet accumulation at the site of vascular injury. In particular, the initial rate of accumulation of platelets is inhibited by elevation of cAMP. Analysis of the kinetics of individual platelets at injury sites using intravital microscopy demonstrates that cAMP directs the rate at which platelets attach to and detach from thrombi. These studies demonstrate that cAMP in circulating platelets controls attachment to and detachment from sites of arteriolar injury. Thus, the status of the intracellular signaling machinery prior to engagement of platelet receptors influences the rate of platelet accumulation during thrombus formation.

scholarly journals Membrane-Permeable Octanoyloxybenzyl-Masked cNMPs As Novel Tools for Non-Invasive Cell Assays

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2960
Author(s):  
Alexandra Ruthenbeck ◽  
Elisa Marangoni ◽  
Björn-Ph. Diercks ◽  
Aileen Krüger ◽  
Alexander Froese ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Adenine Nucleotide ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Chemical Route ◽  
Non Invasive ◽  
Cellular Assays ◽  
Cell Assays ◽  
Enzymatic Activation ◽  
Underlying Processes

Adenine nucleotide (AN) 2nd messengers, such as 3′,5′-cyclic adenosine monophosphate (cAMP), are central elements of intracellular signaling, but many details of their underlying processes remain elusive. Like all nucleotides, cyclic nucleotide monophosphates (cNMPs) are net-negatively charged at physiologic pH which limits their applicability in cell-based settings. Thus, many cellular assays rely on sophisticated techniques like microinjection or electroporation. This setup is not feasible for medium- to high-throughput formats, and the mechanic stress that cells are exposed to raises the probability of interfering artefacts or false-positives. Here, we present a short and flexible chemical route yielding membrane-permeable, bio-reversibly masked cNMPs for which we employed the octanoyloxybenzyl (OB) group. We further show hydrolysis studies on chemical stability and enzymatic activation, and present results of real-time assays, where we used cAMP and Ca2+ live cell imaging to demonstrate high permeability and prompt intracellular conversion of some selected masked cNMPs. Based on these results, our novel OB-masked cNMPs constitute valuable precursor-tools for non-invasive studies on intracellular signaling.

scholarly journals Activation of Signaling Cascades by Weak Extremely Low Frequency Electromagnetic Fields

2017 ◽  
Vol 43 (4) ◽  
pp. 1533-1546 ◽  
Author(s):  
Einat Kapri-Pardes ◽  
Tamar Hanoch ◽  
Galia Maik-Rachline ◽  
Manuel Murbach ◽  
Patricia L. Bounds ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Childhood Leukemia ◽  
Low Frequency ◽  
Cell Types ◽  
Signaling Cascades ◽  
Oncogenic Transformation ◽  
Exposure System ◽  
Extremely Low Frequency ◽  
Mitogen Activated Protein ◽  
Field Strengths

Background/Aims: Results from recent studies suggest that extremely low frequency magnetic fields (ELF-MF) interfere with intracellular signaling pathways related to proliferative control. The mitogen-activated protein kinases (MAPKs), central signaling components that regulate essentially all stimulated cellular processes, include the extracellular signal-regulated kinases 1/2 (ERK1/2) that are extremely sensitive to extracellular cues. Anti-phospho-ERK antibodies serve as a readout for ERK1/2 activation and are able to detect minute changes in ERK stimulation. The objective of this study was to explore whether activation of ERK1/2 and other signaling cascades can be used as a readout for responses of a variety of cell types, both transformed and non-transformed, to ELF-MF. Methods: We applied ELF-MF at various field strengths and time periods to eight different cell types with an exposure system housed in a tissue culture incubator and followed the phosphorylation of MAPKs and Akt by western blotting. Results: We found that the phosphorylation of ERK1/2 is increased in response to ELF-MF. However, the phosphorylation of ERK1/2 is likely too low to induce ELF-MF-dependent proliferation or oncogenic transformation. The p38 MAPK was very slightly phosphorylated, but JNK or Akt were not. The effect on ERK1/2 was detected for exposures to ELF-MF strengths as low as 0.15 µT and was maximal at ∼10 µT. We also show that ERK1/2 phosphorylation is blocked by the flavoprotein inhibitor diphenyleneiodonium, indicating that the response to ELF-MF may be exerted via NADP oxidase similar to the phosphorylation of ERK1/2 in response to microwave radiation. Conclusions: Our results further indicate that cells are responsive to ELF-MF at field strengths much lower than previously suspected and that the effect may be mediated by NADP oxidase. However, the small increase in ERK1/2 phosphorylation is probably insufficient to affect proliferation and oncogenic transformation. Therefore, the results cannot be regarded as proof of the involvement of ELF-MF in cancer in general or childhood leukemia in particular.

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