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Inefficient constitutive inhibition of P2X3 receptors by brain natriuretic peptide system contributes to sensitization of trigeminal sensory neurons in a genetic mouse model of familial hemiplegic migraine.
Mol Pain 2016; 12MP

Abstract

BACKGROUND

On trigeminal ganglion neurons, pain-sensing P2X3 receptors are constitutively inhibited by brain natriuretic peptide via its natriuretic peptide receptor-A. This inhibition is associated with increased P2X3 serine phosphorylation and receptor redistribution to non-lipid raft membrane compartments. The natriuretic peptide receptor-A antagonist anantin reverses these effects. We studied whether P2X3 inhibition is dysfunctional in a genetic familial hemiplegic migraine type-1 model produced by introduction of the human pathogenic R192Q missense mutation into the mouse CACNA1A gene (knock-in phenotype). This model faithfully replicates several properties of familial hemiplegic migraine type-1, with gain-of-function of CaV2.1 Ca(2+) channels, raised levels of the algogenic peptide calcitonin gene-related peptide, and enhanced activity of P2X3 receptors in trigeminal ganglia.

RESULTS

In knock-in neurons, anantin did not affect P2X3 receptor activity, membrane distribution, or serine phosphorylation level, implying ineffective inhibition by the constitutive brain natriuretic peptide/natriuretic peptide receptor-A pathway. However, expression and functional properties of this pathway remained intact together with its ability to downregulate TRPV1 channels. Reversing the familial hemiplegic migraine type-1 phenotype with the CaV2.1-specific antagonist, ω-agatoxin IVA restored P2X3 activity to wild-type level and enabled the potentiating effects of anantin again. After blocking calcitonin gene-related peptide receptors, P2X3 receptors exhibited wild-type properties and were again potentiated by anantin.

CONCLUSIONS

P2X3 receptors on mouse trigeminal ganglion neurons are subjected to contrasting modulation by inhibitory brain natriuretic peptide and facilitatory calcitonin gene-related peptide that both operate via complex intracellular signaling. In the familial hemiplegic migraine type-1 migraine model, the action of calcitonin gene-related peptide appears to prevail over brain natriuretic peptide, thus suggesting that peripheral inhibition of P2X3 receptors becomes insufficient and contributes to trigeminal pain sensitization.

Authors+Show Affiliations

Neuroscience Department, International School for Advanced Studies (SISSA), Trieste, Italy.Neuroscience Department, International School for Advanced Studies (SISSA), Trieste, Italy.Neuroscience Department, International School for Advanced Studies (SISSA), Trieste, Italy.Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands.Neuroscience Department, International School for Advanced Studies (SISSA), Trieste, Italy nistri@sissa.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27175010

Citation

Marchenkova, Anna, et al. "Inefficient Constitutive Inhibition of P2X3 Receptors By Brain Natriuretic Peptide System Contributes to Sensitization of Trigeminal Sensory Neurons in a Genetic Mouse Model of Familial Hemiplegic Migraine." Molecular Pain, vol. 12, 2016.
Marchenkova A, Vilotti S, Ntamati N, et al. Inefficient constitutive inhibition of P2X3 receptors by brain natriuretic peptide system contributes to sensitization of trigeminal sensory neurons in a genetic mouse model of familial hemiplegic migraine. Mol Pain. 2016;12.
Marchenkova, A., Vilotti, S., Ntamati, N., van den Maagdenberg, A. M., & Nistri, A. (2016). Inefficient constitutive inhibition of P2X3 receptors by brain natriuretic peptide system contributes to sensitization of trigeminal sensory neurons in a genetic mouse model of familial hemiplegic migraine. Molecular Pain, 12, doi:10.1177/1744806916646110.
Marchenkova A, et al. Inefficient Constitutive Inhibition of P2X3 Receptors By Brain Natriuretic Peptide System Contributes to Sensitization of Trigeminal Sensory Neurons in a Genetic Mouse Model of Familial Hemiplegic Migraine. Mol Pain. 2016;12 PubMed PMID: 27175010.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inefficient constitutive inhibition of P2X3 receptors by brain natriuretic peptide system contributes to sensitization of trigeminal sensory neurons in a genetic mouse model of familial hemiplegic migraine. AU - Marchenkova,Anna, AU - Vilotti,Sandra, AU - Ntamati,Niels, AU - van den Maagdenberg,Arn Mjm, AU - Nistri,Andrea, Y1 - 2016/05/12/ PY - 2015/12/30/received PY - 2016/03/23/accepted PY - 2016/5/14/entrez PY - 2016/5/14/pubmed PY - 2016/12/27/medline KW - Trigeminal ganglia KW - adenosine triphosphate (ATP) KW - calcitonin gene-related peptide KW - familial hemiplegic migraine type-1 KW - lipid raft KW - nociception KW - purinergic receptor JF - Molecular pain JO - Mol Pain VL - 12 N2 - BACKGROUND: On trigeminal ganglion neurons, pain-sensing P2X3 receptors are constitutively inhibited by brain natriuretic peptide via its natriuretic peptide receptor-A. This inhibition is associated with increased P2X3 serine phosphorylation and receptor redistribution to non-lipid raft membrane compartments. The natriuretic peptide receptor-A antagonist anantin reverses these effects. We studied whether P2X3 inhibition is dysfunctional in a genetic familial hemiplegic migraine type-1 model produced by introduction of the human pathogenic R192Q missense mutation into the mouse CACNA1A gene (knock-in phenotype). This model faithfully replicates several properties of familial hemiplegic migraine type-1, with gain-of-function of CaV2.1 Ca(2+) channels, raised levels of the algogenic peptide calcitonin gene-related peptide, and enhanced activity of P2X3 receptors in trigeminal ganglia. RESULTS: In knock-in neurons, anantin did not affect P2X3 receptor activity, membrane distribution, or serine phosphorylation level, implying ineffective inhibition by the constitutive brain natriuretic peptide/natriuretic peptide receptor-A pathway. However, expression and functional properties of this pathway remained intact together with its ability to downregulate TRPV1 channels. Reversing the familial hemiplegic migraine type-1 phenotype with the CaV2.1-specific antagonist, ω-agatoxin IVA restored P2X3 activity to wild-type level and enabled the potentiating effects of anantin again. After blocking calcitonin gene-related peptide receptors, P2X3 receptors exhibited wild-type properties and were again potentiated by anantin. CONCLUSIONS: P2X3 receptors on mouse trigeminal ganglion neurons are subjected to contrasting modulation by inhibitory brain natriuretic peptide and facilitatory calcitonin gene-related peptide that both operate via complex intracellular signaling. In the familial hemiplegic migraine type-1 migraine model, the action of calcitonin gene-related peptide appears to prevail over brain natriuretic peptide, thus suggesting that peripheral inhibition of P2X3 receptors becomes insufficient and contributes to trigeminal pain sensitization. SN - 1744-8069 UR - https://www.unboundmedicine.com/medline/citation/27175010/Inefficient_constitutive_inhibition_of_P2X3_receptors_by_brain_natriuretic_peptide_system_contributes_to_sensitization_of_trigeminal_sensory_neurons_in_a_genetic_mouse_model_of_familial_hemiplegic_migraine_ L2 - http://journals.sagepub.com/doi/full/10.1177/1744806916646110?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -