Role of purinergic signaling in acupunctureinduced analgesia

Zusammenfassung der Projektergebnisse

The project deals with the pain-relevant P2X3, P2X2/3 and P2X7 receptors (Rs). Attachment of ATP to the binding pouch of the trimeric P2X3 or P2X2/3Rs situated between two neighbouring subunits initiates gating movement to open the ion conducting pore. We found that both possible variants of P2X2/3Rs [(P2X2)1/(P2X3)2 and [(P2X2)2/(P2X3)1] are fully functional. Moreover spontaneous tightening of the binding jaw of the P2X3R by inter-subunit cross-linking of cysteine residues substituted at positions not directly involved in agonist binding inhibited agonist-evoked currents, without interfering with subunit assembly of trafficking. ASIC3 and P2X3Rs appeared to form multiprotein complexes possibly participating in the transfer of painful stimuli during simultaneous acidification and ATP release. In the substantia gelatinosa of the spinal cord dorsal horn, astroglial P2X7Rs released glutamate which activated AMPA/NMDA-Rs at nearby neurons causing pain sensation via the involvement of the downstream spinothalamic neurons. P2X7Rs had a favourable effect on recurrent seizures following one-time status epilepticus (SE) in rodents. Pilocarpine-induced SE increased the sensitivity of P2X7Rs at hippocampal subgranular zone (SGZ) neural progenitor cells (NPCs) which give rise to mature granule cells in the dentate gyrus. Apoptosis/necrosis by P2X7R activation decreases the number of ectopic granule cells thought to be responsible for the manifestation of chronic epilepsy.

Projektbezogene Publikationen (Auswahl)

• (2018) The ASIC3/P2X3 cognate receptor is a pain-relevant and ligand-gated cationic channel. Nature communications 9 (1) 1354
  Stephan, Gabriele; Huang, Lumei; Tang, Yong; Vilotti, Sandra; Fabbretti, Elsa; Yu, Ye; Nörenberg, Wolfgang; Franke, Heike; Gölöncsér, Flóra; Sperlágh, Beáta; Dopychai, Anke; Hausmann, Ralf; Schmalzing, Günther; Rubini, Patrizia; Illes, Peter
  
• Astrocyte-neuron interaction in the substantia gelatinosa of the spinal cord dorsal horn via P2X7 receptor-mediated release of glutamate and reactive oxygen species. Glia 62: 1671-1686, 2014
  Ficker, C., Rozmer, K., Kato, E., Ando, R.D., Schumann, L., Krügel, U., Franke, H., Sperlagh, B., Riedel, T., and Illes, P.
  
• Conformational flexibility of the agonist binding jaw of the hP2X3 receptor is a prerequisite for channel opening. Br. J. Pharmacol. 171: 5093-5112, 2014
  Kowalski, M., Hausmann, R., Grohmann, M., Dopychai, A., Franke, H., Nieber, K., Schmalzing, G., Illes, P., and Riedel, T.
  
• Flexible subunit stoichiometry of functional human P2X2/3 heteromeric receptors. Neuropharmacology 99: 115-130, 2015
  Kowalski, M., Hausmann, R., Schmid, J., Dopychai, A., Stephan, G., Tang, Y., Schmalzing, G., Illes, P. and Rubini, P.
  
• Acupuncture-induced analgesia: A neurobiological basis in purinergic signaling. Neuroscientist 22:563-578, 2016
  Tang, Y., Yin, H.Y., Rubini, P., and Illes, P.
  
• Inter-subunit disulfide locking of the human P2X3 receptor elucidates ectodomain movements associated with channel gating. Purinergic Signalling 12: 221-233, 2016
  Stephan, G., Kowalski-Jahn, M., Zens, C., Schmalzing, G., Illes, P., Hausmann, R.
  
• Inter-subunit disulfide locking of the human P2X3 receptor elucidates ectodomain movements associated with channel gating. Purinergic Signalling 12: 221-233, 2016
  Stephan, G., Kowalski-Jahn, M., Zens, C., Schmalzing, G., Illes, P., Hausmann, R.
  
• Developmental changes in P2X7 receptor-sensitivity of astrocytes and neurons in the substantia gelatinosa of mouse spinal cord slice cultures. Neuroscience 349: 195-207, 2017
  Gao, P., Ding, X., Khan, M.T., Rong, W., Franke, H., Illes, P.
  
• Pilocarpine-induced status epilepticus increases the sensitivity of P2X7 and P2Y1 receptors to nucleotides at neural progenitor cells of the juvenile rodent hippocampus. Cerebral Cortex 27: 3568-3585, 2017
  Rozmer, K., Gao, P., Araújo, M.G.L., Khan, M.T., Liu, J., Rong, R., Tang, Y., Franke, H., Krügel, U., Fernandes, M.J.S., Illes, P.
  
• Regulation of adult neural progenitor cell functions by purinergic signaling. Glia 65: 213-230, 2017
  Tang, Y. and Illes, P.