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The Journal of Neuroscience, June 7, 2006, 26(23):6163-6171; doi:10.1523/JNEUROSCI.0647-06.2006

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Development/Plasticity/Repair
Delayed Upregulation of ATP P2X₃ Receptors of Trigeminal Sensory Neurons by Calcitonin Gene-Related Peptide

Elsa Fabbretti, Marianna D'Arco, Alessandra Fabbro, Manuela Simonetti, Andrea Nistri, and Rashid Giniatullin

Neurobiology Sector and Consiglio Nazionale delle Ricerche–Istituto Nazionale di Fisica della Materia Democritos National Simulation Center, International School for Advanced Studies, 34014 Trieste, Italy

Correspondence should be addressed to Dr. Andrea Nistri, Neurobiology Sector, International School for Advanced Studies, via Beirut 4, 34014 Trieste, Italy. Email: nistri{at}sissa.it

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.

Key words: plasticity; pain; purinergic receptor; nociception; neuropeptide; receptor trafficking

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Received Feb. 14, 2006; revised April 20, 2006; accepted April 24, 2006.

Correspondence should be addressed to Dr. Andrea Nistri, Neurobiology Sector, International School for Advanced Studies, via Beirut 4, 34014 Trieste, Italy. Email: nistri{at}sissa.it

This article has been cited by other articles:

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				M. Simonetti, R. Giniatullin, and E. Fabbretti Mechanisms Mediating the Enhanced Gene Transcription of P2X3 Receptor by Calcitonin Gene-related Peptide in Trigeminal Sensory Neurons J. Biol. Chem., July 4, 2008; 283(27): 18743 - 18752. [Abstract] [Full Text] [PDF]

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