title: Enhancement of acid-sensing ion channel activity by metabotropic P2Y UTP receptors in primary sensory neurons.
abstract: Peripheral purinergic signaling plays an important role in nociception. Increasing evidence suggests that metabotropic P2Y receptors are also involved, but little is known about the underlying mechanism. Herein, we report that selective P2Y receptor agonist uridine 5'-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. First, UTP dose-dependently increased the amplitude of ASIC currents. UTP also shifted the concentration-response curve for proton upwards, with a 56.6 ± 6.4% increase of the maximal current response to proton. Second, UTP potentiation of proton-gated currents can be mimicked by adenosine 5'-triphosphate (ATP), but not by P2Y1 receptor agonist ADP. Potentiation of UTP was blocked by P2Y receptor antagonist suramin and by inhibition of intracellular G protein, phospholipase C (PLC), protein kinase C (PKC), or protein interacting with C-kinase 1 (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. 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.
authors.affiliation: Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, People's Republic of China.
authors.forename: Cuixia
authors.initials: C
authors.lastname: Ren
authors.affiliation: Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, People's Republic of China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Gan
authors.affiliation: Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, People's Republic of China.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Qiu
authors.affiliation: Institute of Ion Channels, Department of Pharmacology, Hubei University of Science and Technology, 88 Xianning Road, Xianning, 437100, Hubei, People's Republic of China. wangping_hu@163.com.
authors.forename: Wang-Ping
authors.identifier: http://orcid.org/0000-0003-1870-325X
authors.initials: WP
authors.lastname: Hu
mesh_terms: D062565:Acid Sensing Ion Channels / Q000187:drug effects* / Q000378:metabolism; D000138:Acidosis / Q000503:physiopathology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010146:Pain / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects; D011522:Protons; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D058472:Receptors, Purinergic P2Y1 / Q000187:drug effects; D011984:Sensory Receptor Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013498:Suramin / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D062565:Acid Sensing Ion Channels; D011522:Protons; D058912:Purinergic P2Y Receptor Agonists; D058921:Purinergic P2Y Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D013498:Suramin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D014544:Uridine Triphosphate
keywords: Acid-sensing ion channel; Dorsal root ganglion neuron; Neuronal excitability; P2Y receptor; Pain; Proton-gated current; UTP