Tags

Type your tag names separated by a space and hit enter

Desensitization properties of P2X3 receptors shaping pain signaling.
Front Cell Neurosci 2013; 7:245FC

Abstract

ATP-gated P2X3 receptors are mostly expressed by nociceptive sensory neurons and participate in transduction of pain signals. P2X3 receptors show a combination of fast desensitization onset and slow recovery. Moreover, even low nanomolar agonist concentrations unable to evoke a response, can induce desensitization via a phenomenon called "high affinity desensitization." We have also observed that recovery from desensitization is agonist-specific and can range from seconds to minutes. The recovery process displays unusually high temperature dependence. Likewise, recycling of P2X3 receptors in peri-membrane regions shows unexpectedly large temperature sensitivity. By applying kinetic modeling, we have previously shown that desensitization characteristics of P2X3 receptor are best explained with a cyclic model of receptor operation involving three agonist molecules binding a single receptor and that desensitization is primarily developing from the open receptor state. Mutagenesis experiments suggested that desensitization depends on a certain conformation of the ATP binding pocket and on the structure of the transmembrane domains forming the ion pore. Further molecular determinants of desensitization have been identified by mutating the intracellular N- and C-termini of P2X3 receptor. Unlike other P2X receptors, the P2X3 subtype is facilitated by extracellular calcium that acts via specific sites in the ectodomain neighboring the ATP binding pocket. Thus, substitution of serine275 in this region (called "left flipper") converts the natural facilitation induced by extracellular calcium to receptor inhibition. Given their strategic location in nociceptive neurons and unique desensitization properties, P2X3 receptors represent an attractive target for development of new analgesic drugs via promotion of desensitization aimed at suppressing chronic pain.

Authors+Show Affiliations

1Department of Neurobiology, A. I. Virtanen Institute, University of Eastern Finland Kuopio, Finland.2Department of Neuroscience, International School for Advanced Studies (SISSA), Trieste Italy.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

24367291

Citation

Giniatullin, Rashid, and Andrea Nistri. "Desensitization Properties of P2X3 Receptors Shaping Pain Signaling." Frontiers in Cellular Neuroscience, vol. 7, 2013, p. 245.
Giniatullin R, Nistri A. Desensitization properties of P2X3 receptors shaping pain signaling. Front Cell Neurosci. 2013;7:245.
Giniatullin, R., & Nistri, A. (2013). Desensitization properties of P2X3 receptors shaping pain signaling. Frontiers in Cellular Neuroscience, 7, p. 245. doi:10.3389/fncel.2013.00245.
Giniatullin R, Nistri A. Desensitization Properties of P2X3 Receptors Shaping Pain Signaling. Front Cell Neurosci. 2013 Dec 6;7:245. PubMed PMID: 24367291.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Desensitization properties of P2X3 receptors shaping pain signaling. AU - Giniatullin,Rashid, AU - Nistri,Andrea, Y1 - 2013/12/06/ PY - 2013/10/24/received PY - 2013/11/18/accepted PY - 2013/12/25/entrez PY - 2013/12/25/pubmed PY - 2013/12/25/medline KW - P2X3 receptor KW - desensitization KW - extracellular ATP KW - pain KW - sensory neuron SP - 245 EP - 245 JF - Frontiers in cellular neuroscience JO - Front Cell Neurosci VL - 7 N2 - ATP-gated P2X3 receptors are mostly expressed by nociceptive sensory neurons and participate in transduction of pain signals. P2X3 receptors show a combination of fast desensitization onset and slow recovery. Moreover, even low nanomolar agonist concentrations unable to evoke a response, can induce desensitization via a phenomenon called "high affinity desensitization." We have also observed that recovery from desensitization is agonist-specific and can range from seconds to minutes. The recovery process displays unusually high temperature dependence. Likewise, recycling of P2X3 receptors in peri-membrane regions shows unexpectedly large temperature sensitivity. By applying kinetic modeling, we have previously shown that desensitization characteristics of P2X3 receptor are best explained with a cyclic model of receptor operation involving three agonist molecules binding a single receptor and that desensitization is primarily developing from the open receptor state. Mutagenesis experiments suggested that desensitization depends on a certain conformation of the ATP binding pocket and on the structure of the transmembrane domains forming the ion pore. Further molecular determinants of desensitization have been identified by mutating the intracellular N- and C-termini of P2X3 receptor. Unlike other P2X receptors, the P2X3 subtype is facilitated by extracellular calcium that acts via specific sites in the ectodomain neighboring the ATP binding pocket. Thus, substitution of serine275 in this region (called "left flipper") converts the natural facilitation induced by extracellular calcium to receptor inhibition. Given their strategic location in nociceptive neurons and unique desensitization properties, P2X3 receptors represent an attractive target for development of new analgesic drugs via promotion of desensitization aimed at suppressing chronic pain. SN - 1662-5102 UR - https://www.unboundmedicine.com/medline/citation/24367291/Desensitization_properties_of_P2X3_receptors_shaping_pain_signaling_ L2 - https://dx.doi.org/10.3389/fncel.2013.00245 DB - PRIME DP - Unbound Medicine ER -