Role of extracellular histidines in antagonist sensitivity of the rat P2X4 receptor.
The pharmacological property that most distinguishes rat P2X4 receptors from other P2X receptors is their insensitivity to the purinoceptor antagonists, suramin and pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). The molecular basis of this insensitivity is not known. Here, we investigated the possibility that histidine residues in the extracellular loop of P2X4 receptors may be involved in the antagonist sensitivity of these receptors. We found that histidine mutation H241A in the rat P2X4 receptor produced receptors that are sensitive to suramin and PPADS. In contrast, mutation H140A or H286A did not significantly alter antagonist sensitivity. In addition, mutation H241A in the human P2X4 receptor significantly increased antagonist sensitivity. The results suggest that histidine 241of P2X4 receptors is involved in regulating the antagonist sensitivity of these receptors.
Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-8115, USA.
Keming
K
Xiong
Randall R
RR
Stewart
Forrest F
FF
Weight
Chaoying
C
Li
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005110:Extracellular Space / Q000187:drug effects* / Q000378:metabolism; D006639:Histidine / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016297:Mutagenesis, Site-Directed / Q000502:physiology; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058848:Receptors, Purinergic P2X4; D013498:Suramin / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D014981:Xenopus
C548226:P2RX4 protein, human; C548228:P2rx4 protein, rat; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058848:Receptors, Purinergic P2X4; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D006639:Histidine; D011732:Pyridoxal Phosphate; D013498:Suramin; D000255:Adenosine Triphosphate