Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model

Molecular Pain

Andrea Nistri²  Elsa Fabbretti³  Arn MJM van den Maagdenberg¹  Mayya Sundukova²  Aswini Gnanasekaran² 

[1] Department of Human Genetics, Leiden University Medical Centre, 2300 RC, Leiden, The Netherlands;Neurobiology Sector and Italian Institute of Technology Unit, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy;Laboratory for Environmental Research, University of Nova Gorica, Vipavska 13, PO Box 301, Rožna Dolina, SI-5000, Slovenia

关键词: ATP;    membrane domains;    purinergic signalling;    neuronal sensitisation;   

Others  :  865711
DOI  :  10.1186/1744-8069-7-77

 received in 2011-04-19, accepted in 2011-09-29,  发布年份 2011

【 摘 要 】

Background

A genetic knock-in mouse model expressing the R192Q mutation of the α1-subunit of the Ca_V2.1 channels frequently found in patients with familial hemiplegic migraine shows functional upregulation of ATP-sensitive P2X3 receptors of trigeminal sensory neurons that transduce nociceptive inputs to the brainstem. In an attempt to understand the basic mechanisms linked to the upregulation of P2X3 receptor activity, we investigated the influence of the lipid domain of these trigeminal sensory neurons on receptor compartmentalization and function.

Results

Knock-in neurons were strongly enriched with lipid rafts containing a larger fraction of P2X3 receptors at membrane level. Pretreatment with the Ca_V2.1 channel blocker ω-agatoxin significantly decreased the lipid raft content of KI membranes. After pharmacologically disrupting the cholesterol component of lipid rafts, P2X3 receptors became confined to non-raft compartments and lost their functional potentiation typically observed in KI neurons with whole-cell patch-clamp recording. Following cholesterol depletion, all P2X3 receptor currents decayed more rapidly and showed delayed recovery indicating that alteration of the lipid raft milieu reduced the effectiveness of P2X3 receptor signalling and changed their desensitization process. Kinetic modeling could reproduce the observed data when slower receptor activation was simulated and entry into desensitization was presumed to be faster.

Conclusions

The more abundant lipid raft compartment of knock-in neurons was enriched in P2X3 receptors that exhibited stronger functional responses. These results suggest that the membrane microenvironment of trigeminal sensory neurons is an important factor in determining sensitization of P2X3 receptors and could contribute to a migraine phenotype by enhancing ATP-mediated responses.

【 授权许可】

   
2011 Gnanasekaran et al; licensee BioMed Central Ltd.

【 图 表 】

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