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Agonist‐dependence of recovery from desensitization of P2X 3 receptors provides a novel and sensitive approach for their rapid up or downregulation
Author(s) -
Sokolova Elena,
Skorinkin Andrei,
Fabbretti Elsa,
Masten Lara,
Nistri Andrea,
Giniatullin Rashid
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705701
Subject(s) - desensitization (medicine) , agonist , adenosine triphosphate , purinergic receptor , homologous desensitization , receptor , chemistry , biophysics , adenosine , ppads , medicine , endocrinology , dorsal root ganglion , biology , neuroscience , spinal cord
Fast‐desensitizing P2X 3 receptors of nociceptive dorsol root ganglion (DRG) neurons are thought to mediate pain sensation. Since P2X 3 receptor efficiency is powerfully modulated by desensitization, its underlying properties were studied with patch‐clamp recording. On rat cultured DRG neurons, 2 s application of ATP (EC 50 =1.52 μ M ), ADP (EC 50 =1.1 μ M ) or α , β ‐meATP (EC 50 =1.78 μ M ) produced similar inward currents that fully desensitized, at the same rate, back to baseline. Recovery from desensitization was much slower after ATP and ADP than after α , β ‐meATP and, in all cases, it had sigmoidal time course. By alternating the application of ATP and α , β ‐meATP, we observed complete cross‐desensitization indicating that these agonists activated the same receptors. This notion was confirmed by the similar antagonism induced by 2′, 3′‐O‐(2,4,6,trinitrophenyl)‐adenosine triphosphate (TNP‐ATP). Recovery from desensitization elicited by ATP was unexpectedly shaped by transient application of α , β ‐methylene‐adenosine triphosphate ( α , β ‐meATP), and vice versa . Thus, short‐lasting, full desensitization produced by α , β ‐meATP protected receptors from long‐lasting desensitization induced by subsequent ATP applications. ATP and ADP had similar properties of recovery from desensitization. Low n M concentrations of α , β ‐meATP (unable to evoke membrane currents) could speed up recovery from ATP‐induced desensitization, while low n M concentrations of ATP enhanced it. Ambient ATP levels were found to be in the p M range (52±3 p M ). The phenomenon of cross‐desensitization and protection was reproduced by rP2X 3 receptors expressed by rat osteoblastic cell 17/2.8 or human embryonic kidney cell 293 cells, indicating P2X 3 receptor specificity. It is suggested that transient application of an agonist that generates rapid recovery from desensitization, is a novel, powerful tool to modulate P2X 3 receptor responsiveness to the natural agonist ATP.British Journal of Pharmacology (2004) 141 , 1048–1058. doi: 10.1038/sj.bjp.0705701