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Familial hemiplegic migraine Ca(v)2.1 channel mutation R192Q enhances ATP-gated P2X3 receptor activity of mouse sensory ganglion neurons mediating trigeminal pain.
Mol Pain 2010; 6:48MP

Abstract

BACKGROUND

The R192Q mutation of the CACNA1A gene, encoding for the α1 subunit of voltage-gated P/Q Ca2+ channels (Ca(v)2.1), is associated with familial hemiplegic migraine-1. We investigated whether this gain-of-function mutation changed the structure and function of trigeminal neuron P2X3 receptors that are thought to be important contributors to migraine pain.

RESULTS

Using in vitro trigeminal sensory neurons of a mouse genetic model knockin for the CACNA1A R192Q mutation, we performed patch clamp recording and intracellular Ca2+ imaging that showed how these knockin ganglion neurons generated P2X3 receptor-mediated responses significantly larger than wt neurons. These enhanced effects were reversed by the Ca(v)2.1 blocker ω-agatoxin. We, thus, explored intracellular signalling dependent on kinases and phosphatases to understand the molecular regulation of P2X3 receptors of knockin neurons. In such cells we observed strong activation of CaMKII reversed by ω-agatoxin treatment. The CaMKII inhibitor KN-93 blocked CaMKII phosphorylation and the hyperesponsive P2X3 phenotype. Although no significant difference in membrane expression of knockin receptors was found, serine phosphorylation of knockin P2X3 receptors was constitutively decreased and restored by KN-93. No change in threonine or tyrosine phosphorylation was detected. Finally, pharmacological inhibitors of the phosphatase calcineurin normalized the enhanced P2X3 receptor responses of knockin neurons and increased their serine phosphorylation.

CONCLUSIONS

The present results suggest that the CACNA1A mutation conferred a novel molecular phenotype to P2X3 receptors of trigeminal ganglion neurons via CaMKII-dependent activation of calcineurin that selectively impaired the serine phosphorylation state of such receptors, thus potentiating their effects in transducing trigeminal nociception.

Authors+Show Affiliations

Neurobiology Sector, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy.

Pub Type(s)

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

Language

eng

PubMed ID

20735819

Citation

Nair, Asha, et al. "Familial Hemiplegic Migraine Ca(v)2.1 Channel Mutation R192Q Enhances ATP-gated P2X3 Receptor Activity of Mouse Sensory Ganglion Neurons Mediating Trigeminal Pain." Molecular Pain, vol. 6, 2010, p. 48.
Nair A, Simonetti M, Birsa N, et al. Familial hemiplegic migraine Ca(v)2.1 channel mutation R192Q enhances ATP-gated P2X3 receptor activity of mouse sensory ganglion neurons mediating trigeminal pain. Mol Pain. 2010;6:48.
Nair, A., Simonetti, M., Birsa, N., Ferrari, M. D., van den Maagdenberg, A. M., Giniatullin, R., ... Fabbretti, E. (2010). Familial hemiplegic migraine Ca(v)2.1 channel mutation R192Q enhances ATP-gated P2X3 receptor activity of mouse sensory ganglion neurons mediating trigeminal pain. Molecular Pain, 6, p. 48. doi:10.1186/1744-8069-6-48.
Nair A, et al. Familial Hemiplegic Migraine Ca(v)2.1 Channel Mutation R192Q Enhances ATP-gated P2X3 Receptor Activity of Mouse Sensory Ganglion Neurons Mediating Trigeminal Pain. Mol Pain. 2010 Aug 24;6:48. PubMed PMID: 20735819.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Familial hemiplegic migraine Ca(v)2.1 channel mutation R192Q enhances ATP-gated P2X3 receptor activity of mouse sensory ganglion neurons mediating trigeminal pain. AU - Nair,Asha, AU - Simonetti,Manuela, AU - Birsa,Nicol, AU - Ferrari,Michel D, AU - van den Maagdenberg,Arn M J M, AU - Giniatullin,Rashid, AU - Nistri,Andrea, AU - Fabbretti,Elsa, Y1 - 2010/08/24/ PY - 2010/06/22/received PY - 2010/08/24/accepted PY - 2010/8/26/entrez PY - 2010/8/26/pubmed PY - 2011/1/5/medline SP - 48 EP - 48 JF - Molecular pain JO - Mol Pain VL - 6 N2 - BACKGROUND: The R192Q mutation of the CACNA1A gene, encoding for the α1 subunit of voltage-gated P/Q Ca2+ channels (Ca(v)2.1), is associated with familial hemiplegic migraine-1. We investigated whether this gain-of-function mutation changed the structure and function of trigeminal neuron P2X3 receptors that are thought to be important contributors to migraine pain. RESULTS: Using in vitro trigeminal sensory neurons of a mouse genetic model knockin for the CACNA1A R192Q mutation, we performed patch clamp recording and intracellular Ca2+ imaging that showed how these knockin ganglion neurons generated P2X3 receptor-mediated responses significantly larger than wt neurons. These enhanced effects were reversed by the Ca(v)2.1 blocker ω-agatoxin. We, thus, explored intracellular signalling dependent on kinases and phosphatases to understand the molecular regulation of P2X3 receptors of knockin neurons. In such cells we observed strong activation of CaMKII reversed by ω-agatoxin treatment. The CaMKII inhibitor KN-93 blocked CaMKII phosphorylation and the hyperesponsive P2X3 phenotype. Although no significant difference in membrane expression of knockin receptors was found, serine phosphorylation of knockin P2X3 receptors was constitutively decreased and restored by KN-93. No change in threonine or tyrosine phosphorylation was detected. Finally, pharmacological inhibitors of the phosphatase calcineurin normalized the enhanced P2X3 receptor responses of knockin neurons and increased their serine phosphorylation. CONCLUSIONS: The present results suggest that the CACNA1A mutation conferred a novel molecular phenotype to P2X3 receptors of trigeminal ganglion neurons via CaMKII-dependent activation of calcineurin that selectively impaired the serine phosphorylation state of such receptors, thus potentiating their effects in transducing trigeminal nociception. SN - 1744-8069 UR - https://www.unboundmedicine.com/medline/citation/20735819/Familial_hemiplegic_migraine_Ca_v_2_1_channel_mutation_R192Q_enhances_ATP_gated_P2X3_receptor_activity_of_mouse_sensory_ganglion_neurons_mediating_trigeminal_pain_ L2 - http://journals.sagepub.com/doi/full/10.1186/1744-8069-6-48?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -