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Brain natriuretic peptide constitutively downregulates P2X3 receptors by controlling their phosphorylation state and membrane localization.
Mol Pain 2015; 11:71MP

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+Show Affiliations

Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy. march@sissa.it.Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy. vilotti@sissa.it.Center for Biomedical Sciences and Engineering, University of Nova Gorica, 5000, Nova Gorica, Slovenia. elsa.fabbretti@ung.si.Neuroscience Department, International School for Advanced Studies (SISSA), Via Bonomea 265, 34136, Trieste, Italy. nistri@sissa.it.

Pub Type(s)

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

Language

eng

PubMed ID

26576636

Citation

Marchenkova, Anna, et al. "Brain Natriuretic Peptide Constitutively Downregulates P2X3 Receptors By Controlling Their Phosphorylation State and Membrane Localization." Molecular Pain, vol. 11, 2015, p. 71.
Marchenkova A, Vilotti S, Fabbretti E, et al. Brain natriuretic peptide constitutively downregulates P2X3 receptors by controlling their phosphorylation state and membrane localization. Mol Pain. 2015;11:71.
Marchenkova, A., Vilotti, S., Fabbretti, E., & Nistri, A. (2015). Brain natriuretic peptide constitutively downregulates P2X3 receptors by controlling their phosphorylation state and membrane localization. Molecular Pain, 11, p. 71. doi:10.1186/s12990-015-0074-6.
Marchenkova A, et al. Brain Natriuretic Peptide Constitutively Downregulates P2X3 Receptors By Controlling Their Phosphorylation State and Membrane Localization. Mol Pain. 2015 Nov 14;11:71. PubMed PMID: 26576636.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Brain natriuretic peptide constitutively downregulates P2X3 receptors by controlling their phosphorylation state and membrane localization. AU - Marchenkova,Anna, AU - Vilotti,Sandra, AU - Fabbretti,Elsa, AU - Nistri,Andrea, Y1 - 2015/11/14/ PY - 2015/09/10/received PY - 2015/11/03/accepted PY - 2015/11/19/entrez PY - 2015/11/19/pubmed PY - 2016/9/23/medline SP - 71 EP - 71 JF - Molecular pain JO - Mol Pain VL - 11 N2 - 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. SN - 1744-8069 UR - https://www.unboundmedicine.com/medline/citation/26576636/Brain_natriuretic_peptide_constitutively_downregulates_P2X3_receptors_by_controlling_their_phosphorylation_state_and_membrane_localization_ L2 - http://journals.sagepub.com/doi/full/10.1186/s12990-015-0074-6?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -