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The scaffold protein calcium/calmodulin-dependent serine protein kinase controls ATP release in sensory ganglia upon P2X3 receptor activation and is part of an ATP keeper complex.
J Neurochem 2016; 138(4):587-97JN

Abstract

P2X3 receptors, gated by extracellular ATP, are expressed by sensory neurons and are involved in peripheral nociception and pain sensitization. The ability of P2X3 receptors to transduce extracellular stimuli into neuronal signals critically depends on the dynamic molecular partnership with the calcium/calmodulin-dependent serine protein kinase (CASK). The present work used trigeminal sensory neurons to study the impact that activation of P2X3 receptors (evoked by the agonist α,β-meATP) has on the release of endogenous ATP and how CASK modulates this phenomenon. P2X3 receptor function was followed by ATP efflux via Pannexin1 (Panx1) hemichannels, a mechanism that was blocked by the P2X3 receptor antagonist A-317491, and by P2X3 silencing. ATP efflux was enhanced by nerve growth factor, a treatment known to potentiate P2X3 receptor function. Basal ATP efflux was not controlled by CASK, and carbenoxolone or Pannexin silencing reduced ATP release upon P2X3 receptor function. CASK-controlled ATP efflux followed P2X3 receptor activity, but not depolarization-evoked ATP release. Molecular biology experiments showed that CASK was essential for the transactivation of Panx1 upon P2X3 receptor activation. These data suggest that P2X3 receptor function controls a new type of feed-forward purinergic signaling on surrounding cells, with consequences at peripheral and spinal cord level. Thus, P2X3 receptor-mediated ATP efflux may be considered for the future development of pharmacological strategies aimed at containing neuronal sensitization. P2X3 receptors are involved in sensory transduction and associate to CASK. We have studied in primary sensory neurons the molecular mechanisms downstream P2X3 receptor activation, namely ATP release and partnership with CASK or Panx1. Our data suggest that CASK and P2X3 receptors are part of an ATP keeper complex, with important feed-forward consequences at peripheral and central level.

Authors+Show Affiliations

Center for Biomedical Sciences and Engineering, University of Nova Gorica, Nova Gorica, Slovenia.Center for Biomedical Sciences and Engineering, University of Nova Gorica, Nova Gorica, Slovenia.

Pub Type(s)

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

Language

eng

PubMed ID

27217099

Citation

Bele, Tanja, and Elsa Fabbretti. "The Scaffold Protein Calcium/calmodulin-dependent Serine Protein Kinase Controls ATP Release in Sensory Ganglia Upon P2X3 Receptor Activation and Is Part of an ATP Keeper Complex." Journal of Neurochemistry, vol. 138, no. 4, 2016, pp. 587-97.
Bele T, Fabbretti E. The scaffold protein calcium/calmodulin-dependent serine protein kinase controls ATP release in sensory ganglia upon P2X3 receptor activation and is part of an ATP keeper complex. J Neurochem. 2016;138(4):587-97.
Bele, T., & Fabbretti, E. (2016). The scaffold protein calcium/calmodulin-dependent serine protein kinase controls ATP release in sensory ganglia upon P2X3 receptor activation and is part of an ATP keeper complex. Journal of Neurochemistry, 138(4), pp. 587-97. doi:10.1111/jnc.13680.
Bele T, Fabbretti E. The Scaffold Protein Calcium/calmodulin-dependent Serine Protein Kinase Controls ATP Release in Sensory Ganglia Upon P2X3 Receptor Activation and Is Part of an ATP Keeper Complex. J Neurochem. 2016;138(4):587-97. PubMed PMID: 27217099.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The scaffold protein calcium/calmodulin-dependent serine protein kinase controls ATP release in sensory ganglia upon P2X3 receptor activation and is part of an ATP keeper complex. AU - Bele,Tanja, AU - Fabbretti,Elsa, Y1 - 2016/06/18/ PY - 2016/03/08/received PY - 2016/05/06/revised PY - 2016/05/11/accepted PY - 2016/5/25/entrez PY - 2016/5/25/pubmed PY - 2017/6/21/medline KW - DRG KW - hemichannels KW - pain KW - purinergic signaling KW - sensory neurons SP - 587 EP - 97 JF - Journal of neurochemistry JO - J. Neurochem. VL - 138 IS - 4 N2 - P2X3 receptors, gated by extracellular ATP, are expressed by sensory neurons and are involved in peripheral nociception and pain sensitization. The ability of P2X3 receptors to transduce extracellular stimuli into neuronal signals critically depends on the dynamic molecular partnership with the calcium/calmodulin-dependent serine protein kinase (CASK). The present work used trigeminal sensory neurons to study the impact that activation of P2X3 receptors (evoked by the agonist α,β-meATP) has on the release of endogenous ATP and how CASK modulates this phenomenon. P2X3 receptor function was followed by ATP efflux via Pannexin1 (Panx1) hemichannels, a mechanism that was blocked by the P2X3 receptor antagonist A-317491, and by P2X3 silencing. ATP efflux was enhanced by nerve growth factor, a treatment known to potentiate P2X3 receptor function. Basal ATP efflux was not controlled by CASK, and carbenoxolone or Pannexin silencing reduced ATP release upon P2X3 receptor function. CASK-controlled ATP efflux followed P2X3 receptor activity, but not depolarization-evoked ATP release. Molecular biology experiments showed that CASK was essential for the transactivation of Panx1 upon P2X3 receptor activation. These data suggest that P2X3 receptor function controls a new type of feed-forward purinergic signaling on surrounding cells, with consequences at peripheral and spinal cord level. Thus, P2X3 receptor-mediated ATP efflux may be considered for the future development of pharmacological strategies aimed at containing neuronal sensitization. P2X3 receptors are involved in sensory transduction and associate to CASK. We have studied in primary sensory neurons the molecular mechanisms downstream P2X3 receptor activation, namely ATP release and partnership with CASK or Panx1. Our data suggest that CASK and P2X3 receptors are part of an ATP keeper complex, with important feed-forward consequences at peripheral and central level. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/27217099/The_scaffold_protein_calcium/calmodulin_dependent_serine_protein_kinase_controls_ATP_release_in_sensory_ganglia_upon_P2X3_receptor_activation_and_is_part_of_an_ATP_keeper_complex_ L2 - https://doi.org/10.1111/jnc.13680 DB - PRIME DP - Unbound Medicine ER -