The pain interactome: Connecting pain-specific protein interactions

Jamieson, Daniel; Moss, Andrew; Kennedy, Michael A.; Jones, Sherrie; Nenadić, Goran; Robertson, David L.; Sidders, Ben

doi:10.1016/j.pain.2014.06.020

Cited by 39 publications

(37 citation statements)

References 49 publications

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“…mitochondrial function as well as protein synthesis and maturation. Although this notion is not new and many transcriptional profiling techniques provide a systems-wide view on cellular networks (7,8,29,91), proteome profiling has so far made only minor contributions (92)(93)(94). Undersampling and limited reproducibility inherent to commonly used shotgun proteomics approaches (16 -19) represent major obstacles for proteome-based systems biology.…”

Section: Discussionmentioning

confidence: 99%

Standardized Profiling of The Membrane-Enriched Proteome of Mouse Dorsal Root Ganglia (DRG) Provides Novel Insights Into Chronic Pain

Rouwette

Sondermann

Avenali

et al. 2016

Molecular & Cellular Proteomics

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Chronic pain is a complex disease with limited treatment options. Several profiling efforts have been employed with the aim to dissect its molecular underpinnings. However, generated results are often inconsistent and nonoverlapping, which is largely because of inherent technical constraints. Emerging data-independent acquisition (DIA)-mass spectrometry (MS) has the potential to provide unbiased, reproducible and quantitative proteome mapsa prerequisite for standardization among experiments. Here, we designed a DIA-based proteomics workflow to profile changes in the abundance of dorsal root ganglia (DRG) proteins in two mouse models of chronic pain, inflammatory and neuropathic. We generated a DRG-specific spectral library containing 3067 DRG proteins, which enables their standardized quantification by means of DIA-MS in any laboratory. Using this resource, we profiled 2526 DRG proteins in each biological replicate of both chronic pain models and respective controls with unprecedented reproducibility. We detected numerous differentially regulated proteins, the majority of which exhibited pain model-specificity. Our approach recapitulates known biology and discovers dozens of proteins that have not been characterized in the somatosensory system before. Functional validation experiments and analysis of mouse pain behaviors demonstrate that indeed meaningful protein alterations were discovered. These results illustrate how the application of DIA-MS can open new avenues to achieve the long-awaited standardization in the molecular dissection of pathologies of the somatosensory system.

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Section: Discussionmentioning

confidence: 99%

Standardized Profiling of The Membrane-Enriched Proteome of Mouse Dorsal Root Ganglia (DRG) Provides Novel Insights Into Chronic Pain

Rouwette

Sondermann

Avenali

et al. 2016

Molecular & Cellular Proteomics

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“…These gene changes were measured shortly after the stressful event (30 mins) as well as at the time (24 hours) corresponding with the observed ROS signal following the stressful event. A panel of genes associated with pain and stress (Table 1) was chosen for analysis according to the literature reports of most common alterations associated with neural damage [29–31]. While most genes in the DRG were unchanged in expression following the stressful event, nerve growth factor (NGF) gene expression was decreased immediately following the stress (30 mins) before returning to normal expression levels.…”

Section: Resultsmentioning

confidence: 99%

“…A panel of genes associated with pain and stress was chosen for analysis. This panel was selected based on known gene changes in DRG following nerve constriction (a pain and stress model) to sciatic nerve using microarray [29], RNA-seq [30] and text mining [31] studies. These genes included: protachykinin-1 ( Tac1 ), neuropeptide Y ( Npy ), calcitonin gene-related peptide ( Cgrp ), vascular intestinal peptide ( Vip ), Pituitary adenylate cyclase-activating polypeptide ( Pacap ), Galanin ( Gal ), nerve growth factor ( Ngf ), neurotrophic tyrosine kinase receptor type 1 ( Ntrk1 ), interleukin-6 ( Il6 ), and POU domain, class 4, transcription factor 1 ( Pou4f1 ).…”

Section: Methodsmentioning

confidence: 99%

Imaging of radicals following injury or acute stress in peripheral nerves with activatable fluorescent probes

Zhou

Yan

et al. 2016

Free Radical Biology and Medicine

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Peripheral nerve injury evokes a complex cascade of chemical reactions including generation of molecular radicals. Conversely, the reactions within nerve induced by stress are difficult to directly detect or measure to establish causality. Monitoring these reactions in vivo would enable deeper understanding of the nature of the injury and healing processes. Here, we utilized near-infrared fluorescence molecular probes delivered via intra-neural injection technique to enable live, in vivo imaging of tissue response associated with nerve injury and stress. These initially quenched fluorescent probes featured specific sensitivity to hydroxyl radicals and become fluorescent upon encountering reactive oxygen species (ROS). Intraneurally delivered probes demonstrated rapid activation in injured rat sciatic nerve but minimal activation in normal, uninjured nerve. In addition, these probes reported activation within sciatic nerves of living rats after a stress caused by a pinprick stimulus to the abdomen. This imaging approach was more sensitive to detecting changes within nerves due to the induced stress than other techniques to evaluate cellular and molecular changes. Specifically, neither histological analysis of the sciatic nerves, nor the expression of pain and stress associated genes in dorsal root ganglia could provide statistically significant differences between the control and stressed groups. Overall, the results demonstrate a novel imaging approach to measure ROS in addition to the impact of ROS within nerve in live animals.

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“…16 Assembly into dynamic multi-protein complexes determines and modulates the multiple functions of a single protein and signaling pathways within a cell -a fact that became known as the concept of cellular "molecular machines". [17][18][19] Consequently, identifying the composition of such complexes and deciphering PPI networks can greatly facilitate insights into distinct signaling pathways.…”

Section: Modulation Of Ion Channel and Receptor Function Via Protein-mentioning

confidence: 99%

“…17,81 Nonetheless, the safety and tolerability of each new PPI modulator will have to be carefully investigated, especially when considering the heterogeneity of pain syndromes and the wealth of proteins involved. To this end, advances in several disciplines have to be bundled, such as rationale PPI modulator design, research efforts aimed at understanding the molecular signature underlying defined pathologies, 11,16 screening technologies reflecting these pathological conditions, functional validation of PPI modulation in defined model systems, as well as stratification of chronic pain patients. 17 The combination of these efforts will likely open new avenues to exploiting PPIs for pain therapy.…”

Section: Are Ppi Modulators Effective Safe and Tolerated In Humans?mentioning

confidence: 99%

Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief

et al. 2015

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In the last 2 decades biomedical research has provided great insights into the molecular signatures underlying painful conditions. However, chronic pain still imposes substantial challenges to researchers, clinicians and patients alike. Under pathological conditions, pain therapeutics often lack efficacy and exhibit only minimal safety profiles, which can be largely attributed to the targeting of molecules with key physiological functions throughout the body. In light of these difficulties, the identification of molecules and associated protein complexes specifically involved in chronic pain states is of paramount importance for designing selective interventions. Ion channels and receptors represent primary targets, as they critically shape nociceptive signaling from the periphery to the brain. Moreover, their function requires tight control, which is usually implemented by protein-protein interactions (PPIs). Indeed, manipulation of such PPIs entails the modulation of ion channel activity with widespread implications for influencing nociceptive signaling in a more specific way. In this review, we highlight recent advances in modulating ion channels and receptors via their PPI networks in the pursuit of relieving chronic pain. Moreover, we critically discuss the potential of targeting PPIs for developing novel pain therapies exhibiting higher efficacy and improved safety profiles.

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The pain interactome: Connecting pain-specific protein interactions

Abstract: SummaryProtein interactions from painful states form a coherent network that can be used to inform further study. We identify proteins key to painful subnetworks.

Cited by 39 publications

References 49 publications

Standardized Profiling of The Membrane-Enriched Proteome of Mouse Dorsal Root Ganglia (DRG) Provides Novel Insights Into Chronic Pain

Standardized Profiling of The Membrane-Enriched Proteome of Mouse Dorsal Root Ganglia (DRG) Provides Novel Insights Into Chronic Pain

Imaging of radicals following injury or acute stress in peripheral nerves with activatable fluorescent probes

Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief

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