Guanine-induced inhibition of renal Na+-ATPase activity: Evidence for the involvement of the Gi protein-coupled receptor

There is some evidence to show a possible role of guanosine in the modulation of cellular function, in particular, in the neuronal system. However, nothing is known about the role of guanine in renal function. The aim of the present work was to investigate the role of guanine on modulation of Na+-ATPase activity in isolated basolateral membrane (BLM) of the renal cortex. Guanine inhibited the enzyme activity in a dose-dependent manner with maximal effect (56%) obtained at 10−6 M. This effect was reversed by DPCPX (8-cyclopentyl-1,3-dipropylxanthine), an antagonist of A1 receptors, but it was not changed by 10−8 M DMPX (3,7-dimethyl-1-propargylxanthine) or 10−8 M MRS (2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate), antagonists of A2 and A3 receptors, respectively. Furthermore, it was observed that guanine increased [γ-35S]GTP-specific binding with the maximal effect observed at 10−6 M and this effect was abolished by 10−6 M GDPβS. The inhibitory effect of 10−6 M guanine on Na+-ATPase activity was reversed by 10−6 M GDPβS, 10−6 M forskolin, 10−6 M pertussis toxin and 10−8 M cholera toxin. These results indicate that guanine binds to a DPCPX-sensitive receptor promoting the activation of Gi protein and leading to a decrease in cAMP level and, consequently, inhibition of BLM Na+-ATPase activity.