18 research outputs found
Differential mechanism of TRPV1 sensitization in peptidergic and nonpeptidergic nociceptors
No full textEl canal TRPV1 es un receptor polimodal, no selectivo a cationes, el cual actúa como principal integrador del estímulo doloroso en nociceptores. Durante la inflamación, los mediadores inflamatorios liberados actúan sobre TRPV1 provocando una excitabilidad aumentada del nociceptor y una hiperalgesia térmica. La sensibilización inflamatoria aguda de TRPV1 conlleva tanto la modificación de las propiedades de apertura del canal (“gating”) por fosforilación como al reclutamiento de nuevos canales a la membrana neuronal. La movilización del canal TRPV1 a la membrana plasmática provocada por algunos mediadores pro-inflamatorios tiene lugar a través de exocitosis dependiente de SNARE, aunque el mecanismo exacto no ha sido todavía esclarecido.
Con el fin de elucidar dicho mecanismo de exocitosis, nos planteamos la hipótesis de que el reclutamiento inflamatorio del canal TRPV1 ocurría únicamente en la subpoblación neuronal que contiene los neuropéptidos sustancia P (SP) y el péptido relacionado con el gen calcitonina (CGRP), también denominada nociceptores peptidérgicos. Así pues, se ha investigado la sensibilización inflamatoria del canal TRPV1 inducida por los agentes pro-inflamatorios Trifosfato de adenosina (ATP) y Bradiquinina (BK) en cultivos de nociceptores tanto peptidérgicos como no peptidérgicos. Para ello, se ha llevado a cabo el análisis funcional del canal TRPV1 empleando técnicas de electrofisiología patch clamp y MEA (matriz de microelectrodos). Nuestros resultados muestran que la inhibición de la exocitosis neuronal por parte del péptido DD04107 provoca una disminución en la sensibilización de TRPV1 inducida por los agentes pro- inflamatorios ATP y BK únicamente en la subpoblación peptidérgica. Además, la eliminación de la expresión de αCGRP también conduce a la reducción de la sensibilización inflamatoria de TRPV1. Así pues, este estudio revela que tanto ATP como BK inducen la exocitosis regulada de TRPV1 en nociceptores peptidérgicos donde αCGRP juega un papel significativo. Además, nuestros resultados validan el potencial terapéutico del péptido DD04107 en la disminución del dolor inflamatorio a través de la modulación de la exocitosis regulada de TRPV1.TRPV1 is a polymodal, non selective cation channel which acts as a major integrator of painful stimuli in nociceptors. During inflammation, the release of inflammatory mediators act on TRPV1 leading to enhanced nociceptor excitability and thermal hyperalgesia. Acute inflammatory sensitization of TRPV1 involves both the modification of channel gating properties by phosphorylation and recruitment of new channels to the neuronal surface. Mobilization of TRPV1 channel to the plasma membrane by some pro- inflammatory mediators occurs through SNARE-dependent exocytosis, but the exact mechanism involved remains to be elucidated. We hypothesize that the inflammatory recruitment of channels occurs in the neuronal subpopulation which contains neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP), also called peptidergic nociceptors.
Therefore, we have investigated the underlying mechanism of pro- inflammatory mediators Adenosine triphosphate (ATP) and Bradykinin (BK) induced inflammatory sensitization of TRPV1 in cultured nociceptors containing both peptidergic and nonpeptidergic subpopulations. We have performed functional analysis using patch clamp electrophysiology and micro electrode array (MEA) technique. We found that the inhibition of neuronal exocytosis results in decreased inflammatory sensitization of TRPV1 induced by both ATP and Bradykinin in peptidergic nociceptors where membrane recruitment of the channel is essential. In addition, knocking out of αCGRP leads to the reduction of inflammatory sensitization of TRPV1.
Hence, this study reveals that both ATP and Bradykinin induces regulated exocytosis of TRPV1 in peptidergic nociceptors where αCGRP plays a significant role. Furthermore, our result validates the therapeutic potential of DD04107 on lessening inflammatory pain through modulation of regulated exocytosis of TRPV1
Author and Owner Intersection in Sound Recordings in The Copyright Act of India
No full text245-250The present work focuses on the intersection of author and owner concerning sound recordings. The interpretation of copyright law on the author and owner intersection by the Court's are rather varied. It may be because the restricted issues at its hand lead the courts. More particularly, interpretation of provisos (b) and (c) of Section 17 of The Copyright Act, 1957 leads to differing interpretations by the Courts. The present analysis is made by studying three recent judgments to understand the author and owner conflicts of sound recordings
Bradykinin Induces TRPV1 Exocytotic Recruitment in Peptidergic Nociceptors
No full textTransient receptor potential vanilloid I (TRPV1) sensitization in peripheral nociceptors
is a prominent phenomenon that occurs in inflammatory pain conditions. Pro-algesic
agents can potentiate TRPV1 activity in nociceptors through both stimulation of its
channel gating and mobilization of channels to the neuronal surface in a context
dependent manner. A recent study reported that ATP-induced TRPV1 sensitization
in peptidergic nociceptors involves the exocytotic release of channels trafficked by
large dense core vesicles (LDCVs) that cargo alpha-calcitonin gene related peptide
alpha (αCGRP). We hypothesized that, similar to ATP, bradykinin may also use
different mechanisms to sensitize TRPV1 channels in peptidergic and non-peptidergic
nociceptors. We found that bradykinin notably enhances the excitability of peptidergic
nociceptors, and sensitizes TRPV1, primarily through the bradykinin receptor 2 pathway.
Notably, bradykinin sensitization of TRPV1 in peptidergic nociceptors was significantly
blocked by inhibiting Ca2+-dependent neuronal exocytosis. In addition, silencing
αCGRP gene expression, but not substance P, drastically reduced bradykinin-induced
TRPV1 sensitization in peptidergic nociceptors. Taken together, these findings indicate
that bradykinin-induced sensitization of TRPV1 in peptidergic nociceptors is partially
mediated by the exocytotic mobilization of new channels trafficked by αCGRP loaded LDCVs to the neuronal membrane. Our findings further imply a central role
of αCGRP peptidergic nociceptors in peripheral algesic sensitization, and substantiate
that inhibition of LDCVs exocytosis is a valuable therapeutic strategy to treat pain, as
it concurrently reduces the release of pro-inflammatory peptides and the membrane
recruitment of thermoTRP channel
Reduce the complexity of the E-learning authoring process
No full textFor every problem, there is one solution which is simple, neat, and wrong. The production of E-Learning contents is today the largest cost factor in the E-Learning and also the major issue of insecurity. This is an obstacle with the further propagation of the E-Learning. At present there are hardly visible numbers of tools to the production of E-Leaning contents. Besides the partial very high prices for this software they have the deficiency that they are usable only after a training course phase by the E-Learning author due to their complexity and its extent. The new challenge for designers and the researchers is to develop software tools for effective E-Learning. This Master thesis proposes an E-learning authoring tool which automatically uploads the file (OpenOffice document) which is selected by the enduser to the LMS/server. It also narrates how the content and the metadata are transformed as a SCORM package as well as its simplicity comparing to the other tools
αCGRP is essential for algesic exocytotic mobilization of TRPV1 channels in peptidergic nociceptors
No full textProalgesic sensitization of peripheral nociceptors in painful syn-dromes is a complex molecular process poorly understood thatinvolves mobilization of thermosensory receptors to the neuronalsurface. However, whether recruitment of vesicular thermoTRPchannels is a general mechanism underlying sensitization of allnociceptor types or is subtype-specific remains controversial. Wereport that sensitization-induced Ca2+-dependent exocytotic inser-tion of transient receptor potential vanilloid 1 (TRPV1) receptors tothe neuronal plasma membrane is a mechanism specifically usedby peptidergic nociceptors to potentiate their excitability. Notably,we found that TRPV1 is present in large dense-core vesicles(LDCVs) that were mobilized to the neuronal surface in responseto a sensitizing insult. Deletion or silencing of calcitonin-gene–related peptide alpha (αCGRP) gene expression drastically reducedproalgesic TRPV1 potentiation in peptidergic nociceptors by abro-gating its Ca2+-dependent exocytotic recruitment. These findingsuncover a context-dependent molecular mechanism of TRPV1 alge-sic sensitization and a previously unrecognized role of αCGRP inLDCV mobilization in peptidergic nociceptors. Furthermore, theseresults imply that concurrent secretion of neuropeptides and chan-nels in peptidergic C-type nociceptors facilitates a rapid modula-tion of pain signalin
Trafficking of ThermoTRP Channels
No full textThermoTRP channels (thermoTRPs) define a subfamily of the transient receptor potential (TRP) channels that are activated by changes in the environmental temperature, from noxious cold to injurious heat. Acting as integrators of several stimuli and signalling pathways, dysfunction of these channels contributes to several pathological states. The surface expression of thermoTRPs is controlled by both, the constitutive and regulated vesicular trafficking. Modulation of receptor surface density during pathological processes is nowadays considered as an interesting therapeutic approach for management of diseases, such as chronic pain, in which an increased trafficking is associated with the pathological state. This review will focus on the recent advances trafficking of the thermoTRP channels, TRPV1, TRPV2, TRPV4, TRPM3, TRPM8 and TRPA1, into/from the plasma membrane. Particularly, regulated membrane insertion of thermoTRPs channels contributes to a fine tuning of final channel activity, and indeed, it has resulted in the development of novel therapeutic approaches with successful clinical results such as disruption of SNARE-dependent exocytosis by botulinum toxin or botulinomimetic peptides
Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation
No full textFull author list omitted for brevity. For the full list of authors, see article.Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field
A Novel Agonist of the Type 1 Lysophosphatidic Acid Receptor (LPA1), UCM-05194, Shows Efficacy in Neuropathic Pain Amelioration
No full textABSTRACT: Neuropathic pain (NP) is a complex chronic
pain state with a prevalence of almost 10% in the general
population. Pharmacological options for NP are limited and
weakly effective, so there is a need to develop more efficacious
NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA1) receptor is a crucial factor in the initiation of
NP. Hence, it is conceivable that a functional antagonism
strategy could lead to NP mitigation. Here we describe a new
series of LPA1 agonists among which derivative (S)-17
(UCM-05194) stands out as the most potent and selective
LPA1 receptor agonist described so far (Emax = 118%, EC50 =
0.24 μM, KD = 19.6 nM; inactive at autotaxin and LPA2−6 receptors). This compound induces characteristic LPA1-mediated
cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons
and to an efficacious attenuation of the pain perception in an in vivo model of NP.Depto. de Química OrgánicaFac. de Ciencias QuímicasTRUEpu
