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.

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: Anna Marchenkova, Sandra Vilotti, Niels Ntamati, Arn Mjm van den Maagdenberg, Andrea Nistri
• Journal: Molecular pain (Mol Pain) Vol. 12 ( 2016) ISSN: 1744-8069 [Electronic] United States
• PMID: 27175010 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2016.

Chemical References

• Calcitonin Gene-Related Peptide Receptor Antagonists
• Peptides, Cyclic
• Purinergic P2X Receptor Antagonists
• Receptors, Calcitonin Gene-Related Peptide
• Receptors, Purinergic P2X3
• TRPV Cation Channels
• TRPV1 protein, mouse
• omega-Agatoxin IVA
• Natriuretic Peptide, Brain
• anantin
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor A

Topics

• Animals
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Disease Models, Animal
• Gene Knock-In Techniques
• Mice
• Migraine with Aura (genetics, metabolism, pathology)
• Models, Biological
• Natriuretic Peptide, Brain (metabolism)
• Peptides, Cyclic (pharmacology)
• Phenotype
• Purinergic P2X Receptor Antagonists (pharmacology)
• Receptors, Atrial Natriuretic Factor (metabolism)
• Receptors, Calcitonin Gene-Related Peptide (metabolism)
• Receptors, Purinergic P2X3 (metabolism)
• Sensory Receptor Cells (drug effects, metabolism, pathology)
• TRPV Cation Channels (metabolism)
• Trigeminal Ganglion (drug effects, metabolism, pathology)
• omega-Agatoxin IVA (pharmacology)