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Neutralization of nerve growth factor induces plasticity of ATP-sensitive P2X3 receptors of nociceptive trigeminal ganglion neurons.
J Neurosci 2007; 27(31):8190-201JN

Abstract

The molecular mechanisms of migraine pain are incompletely understood, although migraine mediators such as NGF and calcitonin gene-related peptide (CGRP) are believed to play an algogenic role. Although NGF block is proposed as a novel analgesic approach, its consequences on nociceptive purinergic P2X receptors of trigeminal ganglion neurons remain unknown. We investigated whether neutralizing NGF might change the function of P2X3 receptors natively coexpressed with NGF receptors on cultured mouse trigeminal neurons. Treatment with an NGF antibody (24 h) decreased P2X3 receptor-mediated currents and Ca2+ transients, an effect opposite to exogenously applied NGF. Recovery from receptor desensitization was delayed by anti-NGF treatment without changing desensitization onset. NGF neutralization was associated with decreased threonine phosphorylation of P2X3 subunits, presumably accounting for their reduced responses and slower recovery. Anti-NGF treatment could also increase the residual current typical of heteromeric P2X2/3 receptors, consistent with enhanced membrane location of P2X2 subunits. This possibility was confirmed with cross-linking and immunoprecipitation studies. NGF neutralization also led to increased P2X2e splicing variant at mRNA and membrane protein levels. These data suggest that NGF controlled plasticity of P2X3 subunits and their membrane assembly with P2X2 subunits. Despite anti-NGF treatment, CGRP could still enhance P2X3 receptor activity, indicating separate NGF- or CGRP-mediated mechanisms to upregulate P2X3 receptors. In an in vivo model of mouse trigeminal pain, anti-NGF pretreatment suppressed responses evoked by P2X3 receptor activation. Our findings outline the important contribution by NGF signaling to nociception of trigeminal sensory neurons, which could be counteracted by anti-NGF pretreatment.

Authors+Show Affiliations

Neurobiology Sector, International School for Advanced Studies, 34014 Trieste, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17670966

Citation

D'Arco, Marianna, et al. "Neutralization of Nerve Growth Factor Induces Plasticity of ATP-sensitive P2X3 Receptors of Nociceptive Trigeminal Ganglion Neurons." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 27, no. 31, 2007, pp. 8190-201.
D'Arco M, Giniatullin R, Simonetti M, et al. Neutralization of nerve growth factor induces plasticity of ATP-sensitive P2X3 receptors of nociceptive trigeminal ganglion neurons. J Neurosci. 2007;27(31):8190-201.
D'Arco, M., Giniatullin, R., Simonetti, M., Fabbro, A., Nair, A., Nistri, A., & Fabbretti, E. (2007). Neutralization of nerve growth factor induces plasticity of ATP-sensitive P2X3 receptors of nociceptive trigeminal ganglion neurons. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 27(31), pp. 8190-201.
D'Arco M, et al. Neutralization of Nerve Growth Factor Induces Plasticity of ATP-sensitive P2X3 Receptors of Nociceptive Trigeminal Ganglion Neurons. J Neurosci. 2007 Aug 1;27(31):8190-201. PubMed PMID: 17670966.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neutralization of nerve growth factor induces plasticity of ATP-sensitive P2X3 receptors of nociceptive trigeminal ganglion neurons. AU - D'Arco,Marianna, AU - Giniatullin,Rashid, AU - Simonetti,Manuela, AU - Fabbro,Alessandra, AU - Nair,Asha, AU - Nistri,Andrea, AU - Fabbretti,Elsa, PY - 2007/8/3/pubmed PY - 2007/8/29/medline PY - 2007/8/3/entrez SP - 8190 EP - 201 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 27 IS - 31 N2 - The molecular mechanisms of migraine pain are incompletely understood, although migraine mediators such as NGF and calcitonin gene-related peptide (CGRP) are believed to play an algogenic role. Although NGF block is proposed as a novel analgesic approach, its consequences on nociceptive purinergic P2X receptors of trigeminal ganglion neurons remain unknown. We investigated whether neutralizing NGF might change the function of P2X3 receptors natively coexpressed with NGF receptors on cultured mouse trigeminal neurons. Treatment with an NGF antibody (24 h) decreased P2X3 receptor-mediated currents and Ca2+ transients, an effect opposite to exogenously applied NGF. Recovery from receptor desensitization was delayed by anti-NGF treatment without changing desensitization onset. NGF neutralization was associated with decreased threonine phosphorylation of P2X3 subunits, presumably accounting for their reduced responses and slower recovery. Anti-NGF treatment could also increase the residual current typical of heteromeric P2X2/3 receptors, consistent with enhanced membrane location of P2X2 subunits. This possibility was confirmed with cross-linking and immunoprecipitation studies. NGF neutralization also led to increased P2X2e splicing variant at mRNA and membrane protein levels. These data suggest that NGF controlled plasticity of P2X3 subunits and their membrane assembly with P2X2 subunits. Despite anti-NGF treatment, CGRP could still enhance P2X3 receptor activity, indicating separate NGF- or CGRP-mediated mechanisms to upregulate P2X3 receptors. In an in vivo model of mouse trigeminal pain, anti-NGF pretreatment suppressed responses evoked by P2X3 receptor activation. Our findings outline the important contribution by NGF signaling to nociception of trigeminal sensory neurons, which could be counteracted by anti-NGF pretreatment. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/17670966/Neutralization_of_nerve_growth_factor_induces_plasticity_of_ATP_sensitive_P2X3_receptors_of_nociceptive_trigeminal_ganglion_neurons_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=17670966 DB - PRIME DP - Unbound Medicine ER -