PMID- 18460469
OWN - NLM
STAT- MEDLINE
DCOM- 20080819
LR  - 20211020
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 27
DP  - 2008 Jul 4
TI  - Mechanisms mediating the enhanced gene transcription of P2X3 receptor by 
      calcitonin gene-related peptide in trigeminal sensory neurons.
PG  - 18743-52
LID - 10.1074/jbc.M800296200 [doi]
AB  - 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.
FAU - Simonetti, Manuela
AU  - Simonetti M
AD  - Neurobiology Sector and Italian Institute of Technology Unit, International 
      School for Advanced Studies (SISSA), 34014 Trieste, Italy .
FAU - Giniatullin, Rashid
AU  - Giniatullin R
FAU - Fabbretti, Elsa
AU  - Fabbretti E
LA  - eng
GR  - GGP07032/TI_/Telethon/Italy
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080506
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Creb1 protein, mouse)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (P2rx3 protein, mouse)
RN  - 0 (Receptors, Purinergic P2)
RN  - 0 (Receptors, Purinergic P2X3)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase)
RN  - JHB2QIZ69Z (Calcitonin Gene-Related Peptide)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Calcitonin Gene-Related Peptide/*metabolism
MH  - Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism
MH  - Cells, Cultured
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Gene Expression Regulation/*physiology
MH  - Mice
MH  - Neurons, Afferent/cytology/*metabolism
MH  - Nociceptors/cytology/*metabolism
MH  - Phosphorylation
MH  - Protein Transport/physiology
MH  - Receptors, Purinergic P2/*biosynthesis
MH  - Receptors, Purinergic P2X3
MH  - Transcription, Genetic/physiology
MH  - Trigeminal Ganglion/cytology/*metabolism
EDAT- 2008/05/08 09:00
MHDA- 2008/08/20 09:00
CRDT- 2008/05/08 09:00
PHST- 2008/05/08 09:00 [pubmed]
PHST- 2008/08/20 09:00 [medline]
PHST- 2008/05/08 09:00 [entrez]
AID - S0021-9258(20)81475-6 [pii]
AID - 10.1074/jbc.M800296200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Jul 4;283(27):18743-52. doi: 10.1074/jbc.M800296200. Epub 2008 
      May 6.