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Mutated CaV2.1 channels dysregulate CASK/P2X3 signaling in mouse trigeminal sensory neurons of R192Q Cacna1a knock-in mice.
Mol Pain 2013; 9:62MP

Abstract

BACKGROUND

ATP-gated P2X3 receptors of sensory ganglion neurons are important transducers of pain as they adapt their expression and function in response to acute and chronic nociceptive signals. The present study investigated the role of calcium/calmodulin-dependent serine protein kinase (CASK) in controlling P2X3 receptor expression and function in trigeminal ganglia from Cacna1a R192Q-mutated knock-in (KI) mice, a genetic model for familial hemiplegic migraine type-1.

RESULTS

KI ganglion neurons showed more abundant CASK/P2X3 receptor complex at membrane level, a result that likely originated from gain-of-function effects of R192Q-mutated CaV2.1 channels and downstream enhanced CaMKII activity. The selective CaV2.1 channel blocker ω-Agatoxin IVA and the CaMKII inhibitor KN-93 were sufficient to return CASK/P2X3 co-expression to WT levels. After CASK silencing, P2X3 receptor expression was decreased in both WT and KI ganglia, supporting the role of CASK in P2X3 receptor stabilization. This process was functionally observed as reduced P2X3 receptor currents.

CONCLUSIONS

We propose that, in trigeminal sensory neurons, the CASK/P2X3 complex has a dynamic nature depending on intracellular calcium and related signaling, that are enhanced in a transgenic mouse model of genetic hemiplegic migraine.

Authors+Show Affiliations

Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, Trieste 34136, Italy. Elsa.Fabbretti@ung.si.No affiliation info availableNo affiliation info availableNo 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

24294842

Citation

Gnanasekaran, Aswini, et al. "Mutated CaV2.1 Channels Dysregulate CASK/P2X3 Signaling in Mouse Trigeminal Sensory Neurons of R192Q Cacna1a Knock-in Mice." Molecular Pain, vol. 9, 2013, p. 62.
Gnanasekaran A, Bele T, Hullugundi S, et al. Mutated CaV2.1 channels dysregulate CASK/P2X3 signaling in mouse trigeminal sensory neurons of R192Q Cacna1a knock-in mice. Mol Pain. 2013;9:62.
Gnanasekaran, A., Bele, T., Hullugundi, S., Simonetti, M., Ferrari, M. D., van den Maagdenberg, A. M., ... Fabbretti, E. (2013). Mutated CaV2.1 channels dysregulate CASK/P2X3 signaling in mouse trigeminal sensory neurons of R192Q Cacna1a knock-in mice. Molecular Pain, 9, p. 62. doi:10.1186/1744-8069-9-62.
Gnanasekaran A, et al. Mutated CaV2.1 Channels Dysregulate CASK/P2X3 Signaling in Mouse Trigeminal Sensory Neurons of R192Q Cacna1a Knock-in Mice. Mol Pain. 2013 Dec 2;9:62. PubMed PMID: 24294842.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutated CaV2.1 channels dysregulate CASK/P2X3 signaling in mouse trigeminal sensory neurons of R192Q Cacna1a knock-in mice. AU - Gnanasekaran,Aswini, AU - Bele,Tanja, AU - Hullugundi,Swathi, AU - Simonetti,Manuela, AU - Ferrari,Michael D, AU - van den Maagdenberg,Arn M J M, AU - Nistri,Andrea, AU - Fabbretti,Elsa, Y1 - 2013/12/02/ PY - 2013/06/02/received PY - 2013/11/22/accepted PY - 2013/12/4/entrez PY - 2013/12/4/pubmed PY - 2014/7/18/medline SP - 62 EP - 62 JF - Molecular pain JO - Mol Pain VL - 9 N2 - BACKGROUND: ATP-gated P2X3 receptors of sensory ganglion neurons are important transducers of pain as they adapt their expression and function in response to acute and chronic nociceptive signals. The present study investigated the role of calcium/calmodulin-dependent serine protein kinase (CASK) in controlling P2X3 receptor expression and function in trigeminal ganglia from Cacna1a R192Q-mutated knock-in (KI) mice, a genetic model for familial hemiplegic migraine type-1. RESULTS: KI ganglion neurons showed more abundant CASK/P2X3 receptor complex at membrane level, a result that likely originated from gain-of-function effects of R192Q-mutated CaV2.1 channels and downstream enhanced CaMKII activity. The selective CaV2.1 channel blocker ω-Agatoxin IVA and the CaMKII inhibitor KN-93 were sufficient to return CASK/P2X3 co-expression to WT levels. After CASK silencing, P2X3 receptor expression was decreased in both WT and KI ganglia, supporting the role of CASK in P2X3 receptor stabilization. This process was functionally observed as reduced P2X3 receptor currents. CONCLUSIONS: We propose that, in trigeminal sensory neurons, the CASK/P2X3 complex has a dynamic nature depending on intracellular calcium and related signaling, that are enhanced in a transgenic mouse model of genetic hemiplegic migraine. SN - 1744-8069 UR - https://www.unboundmedicine.com/medline/citation/24294842/Mutated_CaV2_1_channels_dysregulate_CASK/P2X3_signaling_in_mouse_trigeminal_sensory_neurons_of_R192Q_Cacna1a_knock_in_mice_ L2 - http://journals.sagepub.com/doi/full/10.1186/1744-8069-9-62?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -