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
| Autor: | Elsa Fabbretti, Tanja Bele |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Sensory Receptor Cells Biochemistry 03 medical and health sciences Cellular and Molecular Neuroscience Transactivation chemistry.chemical_compound 0302 clinical medicine Adenosine Triphosphate Calmodulin Ganglia Sensory Phenols Animals Polycyclic Compounds CASK Receptor Protein kinase A Chemistry Purinergic signalling Cell biology body regions Mice Inbred C57BL 030104 developmental biology Trigeminal Ganglion Calcium Signal transduction Adenosine triphosphate 030217 neurology & neurosurgery Receptors Purinergic P2X3 Signal Transduction |
| Zdroj: | Journal of neurochemistry. 138(4) |
| ISSN: | 1471-4159 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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