Brain natriuretic peptide constitutively downregulates P2X3 receptors by controlling their phosphorylation state and membrane localization.

Abstract

BACKGROUND:

ATP-gated P2X3 receptors are important transducers of nociceptive stimuli and are almost exclusively expressed by sensory ganglion neurons. In mouse trigeminal ganglion (TG), P2X3 receptor function is unexpectedly enhanced by pharmacological block of natriuretic peptide receptor-A (NPR-A), outlining a potential inhibitory role of endogenous natriuretic peptides in nociception mediated by P2X3 receptors. Lack of change in P2X3 protein expression indicates a complex modulation whose mechanisms for downregulating P2X3 receptor function remain unclear.

RESULTS:

To clarify this process in mouse TG cultures, we suppressed NPR-A signaling with either siRNA of the endogenous agonist BNP, or the NPR-A blocker anantin. Thus, we investigated changes in P2X3 receptor distribution in the lipid raft membrane compartment, their phosphorylation state, as well as their function with patch clamping. Delayed onset of P2X3 desensitization was one mechanism for the anantin-induced enhancement of P2X3 activity. Anantin application caused preferential P2X3 receptor redistribution to the lipid raft compartment and decreased P2X3 serine phosphorylation, two phenomena that were not interdependent. An inhibitor of cGMP-dependent protein kinase and siRNA-mediated knockdown of BNP mimicked the effect of anantin.

CONCLUSIONS:

We demonstrated that in mouse trigeminal neurons endogenous BNP acts on NPR-A receptors to determine constitutive depression of P2X3 receptor function. Tonic inhibition of P2X3 receptor activity by BNP/NPR-A/PKG pathways occurs via two distinct mechanisms: P2X3 serine phosphorylation and receptor redistribution to non-raft membrane compartments. This novel mechanism of receptor control might be a target for future studies aiming at decreasing dysregulated P2X3 receptor activity in chronic pain.

• Authors: Anna Marchenkova, Sandra Vilotti, Elsa Fabbretti, Andrea Nistri
• Journal: Molecular pain (Mol Pain) Vol. 11 Pg. 71 (Nov 14 2015) ISSN: 1744-8069 [Electronic] United States
• PMID: 26576636 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Purinergic P2X3
• Natriuretic Peptide, Brain
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor A

Topics

• Animals
• Chronic Pain (physiopathology)
• Down-Regulation
• Ganglia, Sensory
• Mice
• Natriuretic Peptide, Brain (physiology)
• Nociception (physiology)
• Phosphorylation
• Receptors, Atrial Natriuretic Factor (metabolism)
• Receptors, Purinergic P2X3 (metabolism)
• Signal Transduction
• Trigeminal Ganglion