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Mechanisms mediating the enhanced gene transcription of P2X3 receptor by calcitonin gene-related peptide in trigeminal sensory neurons.
J Biol Chem 2008; 283(27):18743-52JB

Abstract

The molecular mechanisms underlying migraine pain remain unclear and probably require sustained facilitation in pain-sensing P2X(3) receptors gated by extracellular ATP in nociceptive sensory neurons. The major migraine mediator calcitonin gene-related peptide (CGRP) is known to sensitize P2X(3) receptors to increase impulse flow to brainstem trigeminal nuclei. This process is mediated via changes in the expression and function of P2X(3) receptors initially through enhanced trafficking and, later, perhaps through augmented synthesis of P2X(3) receptors. To clarify the mechanisms responsible for CGRP-evoked long lasting alterations in P2X(3) receptors, we used as a model mouse trigeminal ganglion neurons in culture. CGRP activated Ca(2+)-calmodulin-dependent kinase II, which became localized to the perimembrane region and neuronal processes, a phenomenon already apparent after 30 min and accompanied by a parallel increase in cAMP-response element-binding protein (CREB) phosphorylation and nuclear translocation. These effects triggered increased P2X(3) receptor transcription and were prevented by expressing a dominant negative form of CREB. Increased P2X(3) receptor synthesis was partly mediated by endogenous brain-derived neurotrophic factor (BDNF) because of its block by anti-BDNF antibodies and mimicry by exogenous BDNF. Immunocytochemistry experiments indicated distinct subpopulations of BDNF- or CGRP-sensitive trigeminal neurons with only partial overlap. The present data indicate a novel mechanism for enhancing P2X(3) receptor expression and function in trigeminal sensory neurons by CGRP via CREB phosphorylation. BDNF was an intermediate to extend the sensitizing effect of CGRP also to CGRP-insensitive neurons. This combinatorial action could serve as a powerful process to amplify and prolong pain mediated by P2X(3) receptors.

Authors+Show Affiliations

Neurobiology Sector and Italian Institute of Technology Unit, International School for Advanced Studies (SISSA), 34014 Trieste, Italy .No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

18460469

Citation

Simonetti, Manuela, et al. "Mechanisms Mediating the Enhanced Gene Transcription of P2X3 Receptor By Calcitonin Gene-related Peptide in Trigeminal Sensory Neurons." The Journal of Biological Chemistry, vol. 283, no. 27, 2008, pp. 18743-52.
Simonetti M, Giniatullin R, Fabbretti E. Mechanisms mediating the enhanced gene transcription of P2X3 receptor by calcitonin gene-related peptide in trigeminal sensory neurons. J Biol Chem. 2008;283(27):18743-52.
Simonetti, M., Giniatullin, R., & Fabbretti, E. (2008). Mechanisms mediating the enhanced gene transcription of P2X3 receptor by calcitonin gene-related peptide in trigeminal sensory neurons. The Journal of Biological Chemistry, 283(27), pp. 18743-52. doi:10.1074/jbc.M800296200.
Simonetti M, Giniatullin R, Fabbretti E. Mechanisms Mediating the Enhanced Gene Transcription of P2X3 Receptor By Calcitonin Gene-related Peptide in Trigeminal Sensory Neurons. J Biol Chem. 2008 Jul 4;283(27):18743-52. PubMed PMID: 18460469.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanisms mediating the enhanced gene transcription of P2X3 receptor by calcitonin gene-related peptide in trigeminal sensory neurons. AU - Simonetti,Manuela, AU - Giniatullin,Rashid, AU - Fabbretti,Elsa, Y1 - 2008/05/06/ PY - 2008/5/8/pubmed PY - 2008/8/20/medline PY - 2008/5/8/entrez SP - 18743 EP - 52 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 283 IS - 27 N2 - The molecular mechanisms underlying migraine pain remain unclear and probably require sustained facilitation in pain-sensing P2X(3) receptors gated by extracellular ATP in nociceptive sensory neurons. The major migraine mediator calcitonin gene-related peptide (CGRP) is known to sensitize P2X(3) receptors to increase impulse flow to brainstem trigeminal nuclei. This process is mediated via changes in the expression and function of P2X(3) receptors initially through enhanced trafficking and, later, perhaps through augmented synthesis of P2X(3) receptors. To clarify the mechanisms responsible for CGRP-evoked long lasting alterations in P2X(3) receptors, we used as a model mouse trigeminal ganglion neurons in culture. CGRP activated Ca(2+)-calmodulin-dependent kinase II, which became localized to the perimembrane region and neuronal processes, a phenomenon already apparent after 30 min and accompanied by a parallel increase in cAMP-response element-binding protein (CREB) phosphorylation and nuclear translocation. These effects triggered increased P2X(3) receptor transcription and were prevented by expressing a dominant negative form of CREB. Increased P2X(3) receptor synthesis was partly mediated by endogenous brain-derived neurotrophic factor (BDNF) because of its block by anti-BDNF antibodies and mimicry by exogenous BDNF. Immunocytochemistry experiments indicated distinct subpopulations of BDNF- or CGRP-sensitive trigeminal neurons with only partial overlap. The present data indicate a novel mechanism for enhancing P2X(3) receptor expression and function in trigeminal sensory neurons by CGRP via CREB phosphorylation. BDNF was an intermediate to extend the sensitizing effect of CGRP also to CGRP-insensitive neurons. This combinatorial action could serve as a powerful process to amplify and prolong pain mediated by P2X(3) receptors. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/18460469/Mechanisms_mediating_the_enhanced_gene_transcription_of_P2X3_receptor_by_calcitonin_gene_related_peptide_in_trigeminal_sensory_neurons_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=18460469 DB - PRIME DP - Unbound Medicine ER -