Enhancement Of Metabolic P2Y Receptor Agonist UTP On Acid - Sensitive Ion Channels In Primary Sensory Neurons

Obiective: Peripheral purinergic signaling plays an important role in nociception.Increasing evidence suggests that metabotropic P2 Y receptors are also involved, but little is known about the underlying mechanism.Herein,we report that selective P2 Y receptor agonist uridine5′-triphosphate(UTP) can exert an enhancing effect on the functional activity of acid-sensing ion channels(ASICs), key sensors for extracellular protons, in rat dorsal root ganglia(DRG) neurons.Methods:In this study,we explore the mechanism of UTP enhance the acid sensoring iron channels in primary sensory neurons though electrophisological experiments and behavioral experiments at the cell level and animal level,respectively.Results: First,UTP dose-dependently increased the amplitude of ASIC currents.UTP also shifted the on centration–response curve for proton upwards, with a56.6±6.4% increase of the maximal current response to proton. Second, UTP potentiation of proton-gated currents can be mimicked by adenosine5′-tri-phosphate(ATP), but not by P2Y1 receptor agonist ADP. Potentiation of UTP was blocked by P2 Y receptor antagonist suramin and by inhibition of intracellular G-protein,phospho-lipase C(PLC), protein kinase C(PKC), or protein interacting with C-kinase1(PICK1) signaling. Third, UTP altered acidosis-evoked membrane excitability of DRG neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally,UTP dose-dependently exacerbated nociceptive responses to injection of acetic acid in rats.Concusion:These results suggest that UTP enhanced ASIC-mediated currents and nociceptive responses, which reveal a novel peripheral mechanism underlying UTP-sensitive P2Y2 receptor involvement in hyperalgesia by sensitizing ASICs in primary sensory neurons.