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Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model.
Mol Pain 2011; 7:77MP

Abstract

BACKGROUND

A genetic knock-in mouse model expressing the R192Q mutation of the α1-subunit of the Ca(V)2.1 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(V)2.1 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.

Authors+Show Affiliations

Neurobiology Sector and Italian Institute of Technology Unit, International School for Advanced Studies, Trieste, Italy.No 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

21958474

Citation

Gnanasekaran, Aswini, et al. "Lipid Rafts Control P2X3 Receptor Distribution and Function in Trigeminal Sensory Neurons of a Transgenic Migraine Mouse Model." Molecular Pain, vol. 7, 2011, p. 77.
Gnanasekaran A, Sundukova M, van den Maagdenberg AM, et al. Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model. Mol Pain. 2011;7:77.
Gnanasekaran, A., Sundukova, M., van den Maagdenberg, A. M., Fabbretti, E., & Nistri, A. (2011). Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model. Molecular Pain, 7, p. 77. doi:10.1186/1744-8069-7-77.
Gnanasekaran A, et al. Lipid Rafts Control P2X3 Receptor Distribution and Function in Trigeminal Sensory Neurons of a Transgenic Migraine Mouse Model. Mol Pain. 2011 Sep 29;7:77. PubMed PMID: 21958474.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lipid rafts control P2X3 receptor distribution and function in trigeminal sensory neurons of a transgenic migraine mouse model. AU - Gnanasekaran,Aswini, AU - Sundukova,Mayya, AU - van den Maagdenberg,Arn M J M, AU - Fabbretti,Elsa, AU - Nistri,Andrea, Y1 - 2011/09/29/ PY - 2011/04/19/received PY - 2011/09/29/accepted PY - 2011/10/1/entrez PY - 2011/10/1/pubmed PY - 2012/5/12/medline SP - 77 EP - 77 JF - Molecular pain JO - Mol Pain VL - 7 N2 - BACKGROUND: A genetic knock-in mouse model expressing the R192Q mutation of the α1-subunit of the Ca(V)2.1 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(V)2.1 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. SN - 1744-8069 UR - https://www.unboundmedicine.com/medline/citation/21958474/Lipid_rafts_control_P2X3_receptor_distribution_and_function_in_trigeminal_sensory_neurons_of_a_transgenic_migraine_mouse_model_ L2 - http://journals.sagepub.com/doi/full/10.1186/1744-8069-7-77?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -