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Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide.
J Neurosci 2006; 26(23):6163-71JN

Abstract

Recent evidence indicates a key role for the neuropeptide calcitonin gene-related peptide (CGRP) in migraine pain, as demonstrated by the strong analgesic action of CGRP receptor antagonists, although the mechanisms of this effect remain unclear. Most trigeminal nociceptive neurons releasing CGRP also express ATP-activated purinergic P2X3 receptors to transduce pain. To understand whether the CGRP action involves P2X3 receptor modulation, the model of trigeminal nociceptive neurons in culture was used to examine the long-term action of this peptide. Although 79% of CGRP-binding neurons expressed P2X3 receptors, acute application of CGRP did not change P2X3 receptor function. Nevertheless, after 1 h of CGRP treatment, strong enhancement of the amplitude of P2X3 receptor currents was observed together with accelerated recovery from desensitization. Receptor upregulation persisted up to 10 h (despite CGRP washout), was accompanied by increased P2X3 gene transcription, and was fully prevented by the CGRP antagonist CGRP(8-37). Surface biotinylation showed CGRP augmented P2X3 receptor expression, consistent with confocal microscopy data indicating enhanced P2X3 immunoreactivity beneath the neuronal membrane. These results suggest that CGRP stimulated trafficking of P2X3 receptors to the cell-surface membrane. Using pharmacological tools, we demonstrated that this effect of CGRP was dependent on protein kinase A and PKC activation and was prevented by the trafficking inhibitor brefeldin A. Capsaicin-sensitive TRPV1 vanilloid receptors were not upregulated. The present data demonstrate a new form of selective, slow upregulation of nociceptive P2X3 receptors on trigeminal neurons by CGRP. This mechanism might contribute to pain sensitization and represents a model of neuronal plasticity in response to a migraine mediator.

Authors+Show Affiliations

Consiglio Nazionale delle Ricerche, Istituto Nazionale di Fisica della Materia Democritos National Simulation Center, International School for Advanced Studies, 34014 Trieste, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

16763024

Citation

Fabbretti, Elsa, et al. "Delayed Upregulation of ATP P2X3 Receptors of Trigeminal Sensory Neurons By Calcitonin Gene-related Peptide." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 26, no. 23, 2006, pp. 6163-71.
Fabbretti E, D'Arco M, Fabbro A, et al. Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. J Neurosci. 2006;26(23):6163-71.
Fabbretti, E., D'Arco, M., Fabbro, A., Simonetti, M., Nistri, A., & Giniatullin, R. (2006). Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 26(23), pp. 6163-71.
Fabbretti E, et al. Delayed Upregulation of ATP P2X3 Receptors of Trigeminal Sensory Neurons By Calcitonin Gene-related Peptide. J Neurosci. 2006 Jun 7;26(23):6163-71. PubMed PMID: 16763024.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Delayed upregulation of ATP P2X3 receptors of trigeminal sensory neurons by calcitonin gene-related peptide. AU - Fabbretti,Elsa, AU - D'Arco,Marianna, AU - Fabbro,Alessandra, AU - Simonetti,Manuela, AU - Nistri,Andrea, AU - Giniatullin,Rashid, PY - 2006/6/10/pubmed PY - 2006/7/11/medline PY - 2006/6/10/entrez SP - 6163 EP - 71 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 26 IS - 23 N2 - Recent evidence indicates a key role for the neuropeptide calcitonin gene-related peptide (CGRP) in migraine pain, as demonstrated by the strong analgesic action of CGRP receptor antagonists, although the mechanisms of this effect remain unclear. Most trigeminal nociceptive neurons releasing CGRP also express ATP-activated purinergic P2X3 receptors to transduce pain. To understand whether the CGRP action involves P2X3 receptor modulation, the model of trigeminal nociceptive neurons in culture was used to examine the long-term action of this peptide. Although 79% of CGRP-binding neurons expressed P2X3 receptors, acute application of CGRP did not change P2X3 receptor function. Nevertheless, after 1 h of CGRP treatment, strong enhancement of the amplitude of P2X3 receptor currents was observed together with accelerated recovery from desensitization. Receptor upregulation persisted up to 10 h (despite CGRP washout), was accompanied by increased P2X3 gene transcription, and was fully prevented by the CGRP antagonist CGRP(8-37). Surface biotinylation showed CGRP augmented P2X3 receptor expression, consistent with confocal microscopy data indicating enhanced P2X3 immunoreactivity beneath the neuronal membrane. These results suggest that CGRP stimulated trafficking of P2X3 receptors to the cell-surface membrane. Using pharmacological tools, we demonstrated that this effect of CGRP was dependent on protein kinase A and PKC activation and was prevented by the trafficking inhibitor brefeldin A. Capsaicin-sensitive TRPV1 vanilloid receptors were not upregulated. The present data demonstrate a new form of selective, slow upregulation of nociceptive P2X3 receptors on trigeminal neurons by CGRP. This mechanism might contribute to pain sensitization and represents a model of neuronal plasticity in response to a migraine mediator. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/16763024/Delayed_upregulation_of_ATP_P2X3_receptors_of_trigeminal_sensory_neurons_by_calcitonin_gene_related_peptide_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=16763024 DB - PRIME DP - Unbound Medicine ER -