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




Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model - Download this document for free, or read online. Document in PDF available to download.

Molecular Pain

, 7:77

First Online: 29 September 2011Received: 19 April 2011Accepted: 29 September 2011

Abstract

BackgroundA genetic knock-in mouse model expressing the R192Q mutation of the α1-subunit of the CaV2.1 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.

ResultsKnock-in neurons were strongly enriched with lipid rafts containing a larger fraction of P2X3 receptors at membrane level. Pretreatment with the CaV2.1 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.

ConclusionsThe 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.

Keywordsneuronal sensitisation purinergic signalling membrane domains ATP List of abbreviations usedαβ-meATP: α,β-methylATP

CTX-Bcholera toxin B

FHM-1familial hemiplegic migraine type 1

GPIglycosylphosphatidylinositol

MβCDknock-in, KI methyl β-cyclodextrin

PBSphosphate buffered saline

TGtrigeminal ganglia

WTwild type.

Electronic supplementary materialThe online version of this article doi:10.1186-1744-8069-7-77 contains supplementary material, which is available to authorized users.

Aswini Gnanasekaran, Mayya Sundukova contributed equally to this work.

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Author: Aswini Gnanasekaran - Mayya Sundukova - Arn MJM van den Maagdenberg - Elsa Fabbretti - Andrea Nistri

Source: https://link.springer.com/







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