Mutated CaV2.1 channels dysregulate CASK/P2X3 signaling in mouse trigeminal sensory neurons of R192Q Cacna1a knock-in mice

Molecular Pain

Elsa Fabbretti⁵  Andrea Nistri¹  Arn MJM van den Maagdenberg³  Michael D Ferrari⁴  Manuela Simonetti²  Swathi Hullugundi¹  Tanja Bele⁵  Aswini Gnanasekaran¹ 

[1] Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, Trieste 34136, Italy;Present address: Pharmacology Institute, University of Heidelberg Germany Heidelberg, Germany;Department of Human Genetics, Leiden University Medical Center, Leiden RC 2300, The Netherlands;Department of Neurology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands;Center for Biomedical Sciences and Engineering, University of Nova Gorica, Nova Gorica SI-5000, Slovenia

关键词: Migraine;    Trigeminal ganglion;    DRG;    Purinergic signaling;    ATP;    Pain;   

Others  :  862079
DOI  :  10.1186/1744-8069-9-62

 received in 2013-06-02, accepted in 2013-11-22,  发布年份 2013

【 摘 要 】

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 Ca_V2.1 channels and downstream enhanced CaMKII activity. The selective Ca_V2.1 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.

【 授权许可】

   
2013 Gnanasekaran et al.; licensee BioMed Central Ltd.

【 图 表 】

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