MOLECULAR MECHANISMS REGULATING ATP SIGNALING IN MOUSE SENSORY NEURONSTanja Bele
, 2015, doctoral dissertation
Abstract: Coordinated and harmonized neuronal and glial responses to variations in extracellular levels of active soluble mediators such as ATP are essential in controlling neuronal activity. In pathological conditions involving sensory nervous system, elevations in extracellular ATP levels are believed to be one of the main reason for neuronal sensitization.
This notion led us to explore mechanisms of ATP release in sensory ganglia and we found that association among P2X purinergic receptors, their downstream effectors (CASK and CaMKII) and hemichannel Panx1 regulates inhibition of ATP release in basal conditions and that same players are involved in P2X3 receptor evoked-ATP release which globally suggest that even if observed proteins are expressed in different cells, they could be modulated by similar mechanisms and are possibly part of an “ATP-keeper molecular system” that finely regulates extracellular levels of ATP by its sensing and further adjustments of peculiar extracellular concentrations.
Further we showed that P2X3 receptors interact with Panx1 in sensory neurons and that molecular coupling between P2X3, CASK and Panx1 contributes to decoding of the complex purinergic signaling involved in nociception which represents a novel and interesting mechanism of pain regulation that could be precisely targeted in order to alleviate tedious disorders of sensory neurons.
Found in: osebi
Keywords: ATP, ATP release, purinergic signaling, trigeminal ganglion, pain, migraine, P2X3, CASK, Pannexin-1, synaptic strength
Published: 10.12.2015; Views: 4039; Downloads: 193
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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.Elsa Fabbretti
, Tanja Bele
, 2016, original scientific article
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.
Found in: osebi
Keywords: DRG, hemichannels, pain, purinergic signaling, sensory neurons
Published: 19.01.2017; Views: 3035; Downloads: 0
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