The selective P2X purinoceptor agonist, β,γ-methylene-L-adenosine 5′-triphosphate, discriminates between smooth muscle and neuronal P2X purinoceptors
Abstract The effects of the putative selective P2X purinoceptor agonist, β,γ-methylene-l-adenosine 5′-triphosphate (βγme-l-ATP), were determined at rat neuronal and smooth muscle P2X purinoceptors. βγMe-l-ATP had no effect on the extracellularly recorded membrane potential of the rat isolate... Ausführliche Beschreibung
|1. Person:||Trezise, D. J.|
|Weitere Personen:||Michel, A. D.; Grahames, C. B. A.; Khakh, B. S.; Surprenant, A.; Humphrey, P. P. A.|
in Naunyn-Schmiedeberg's archives of pharmacology Vol. 351 (1995), p. 603-609
|Genre:||P2X Purinoceptor, βγ-Methylene-l-ATP, Rat vagus nerve, Nodose ganglion neurones, Rat vas deferens|
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Copyright: Copyright 1995 Springer-Verlag
Abstract The effects of the putative selective P2X purinoceptor agonist, β,γ-methylene-l-adenosine 5′-triphosphate (βγme-l-ATP), were determined at rat neuronal and smooth muscle P2X purinoceptors. βγMe-l-ATP had no effect on the extracellularly recorded membrane potential of the rat isolated vagus nerve preparation at concentrations up to 300 μM. In contrast, the archetypal P2X purinoceptor agonist, α, β methylene ATP (αβmeATP;1–100 μM), produced concentration-related depolarisation responses with a mean EC50 value of 10.8 μM. The depolarising effects of αβmeATP were not attenuated by βγme-l-ATP (100 μM). In voltage clamp experiments on single nodose ganglion neurones, ATP (100 μM), but not βγme-l.-ATP (1–300 μM), evoked rapid ( < 20 ms onset) inward currents when applied using a concentration-clamp method. In receptor binding studies to rat brain membranes, βγme-d-ATP and αβmeATP competed with high affinity for [3H]Lx βmeATP binding sites, with mean pIC50 values of 7.7 and 8.3, respectively. However, βγme-l-ATP possessed low affinity for these sites and competed only at concentrations in excess of 10 μM (mean pIC50 value 4.1). In prostatic segments of the rat vas deferens, βγme-l-ATP (1–100 μM) and αβmeATP (0.3–100 μM) each produced concentration-related contractile responses with mean EC50 values of 17.1 and 3.6 μM, respectively. βγMe-l-ATP (1–10 μM) evoked fast inward currents in freshly dispersed vas deferens smooth muscle cells, indicative of an action at ligand-gated ion channels. Binding sites in vas deferens membranes labelled using 1 nM [3H]αβmeATP exhibited high affinity for ββ γme-l-ATP, αβmeATP and βγme-d-ATP with mean PIC50 values of 7.7, 8.4 and 7.3, respectively. These results indicate that βγme-l-ATP exhibits neither agonist nor antagonist properties at P2X purinoceptors on rat vagal neurones and possesses only very low affinity for [3H]αβmeATP binding sites in rat brain. In contrast, βγme-l-ATP is a potent, high affinity agonist at smooth muscle P2X purinoceptors of the rat vas deferens. This selective agonist action of βγme-l-ATP suggests that P2X purinoceptors in smooth muscle and neurones are different and represent distinct P2X purinoceptor subtypes.