Endogenous GABAA receptor activity suppresses glioma growth.

Although genome alterations driving glioma by fueling cell malignancy have largely been resolved, less is known of the impact of tumor environment on disease progression. Here, we demonstrate functional GABAA receptor-activated currents in human glioblastoma cells and show the existence of a continuous GABA signaling within the tumor cell mass that significantly affects tumor growth and survival expectancy in mouse models. Endogenous GABA released by tumor cells, attenuates proliferation of the glioma cells with enriched expression of stem/progenitor markers and with competence to seed growth of new tumors. Our results suggest that GABA levels rapidly increase in tumors impeding further growth. Thus, shunting chloride ions by a maintained local GABAA receptor activity within glioma cells has a significant impact on tumor development by attenuating proliferation, reducing tumor growth and prolonging survival, a mechanism that may have important impact on therapy resistance and recurrence following tumor resection.

Adenine-induced inhibition of Na(+)-ATPase activity: Evidence for involvement of the Gi protein-coupled receptor in the cAMP signaling pathway.

In the present work, we demonstrate that adenine reduced Na(+)-ATPase activity in isolated basolateral membrane (BLM) of proximal tubule in a dose-dependent manner. Adenine metabolism was ruled out by TLC analysis of the potential [(3)H]adenine derived-metabolites. Specific binding of [(3)H]adenine to isolated BLM was observed in a dose-dependent manner with K(d) and B(max) of 242.6+/-27.6 nM and 2749.9+/-104.9 fmolmg(-1), respectively. Adenine increased the [(35)S]GTPgammaS specific binding and it was completely abolished by 10(-6)M GDPbetaS (G protein inhibitor) but it was not modified by DPCPX, DMPX and MRS1523, selective antagonists for A(1), A(2) and A(3) receptors, respectively. Furthermore, the inhibitory effect of adenine on the Na(+)-ATPase activity was blocked by 10(-6)M GDPbetaS, 1 microg/ml pertussis toxin (Gi protein inhibitor), 10(-6)M foskolin (adenylyl cyclase activator) and 10(-8)M cAMP. These data demonstrate that adenine inhibits the proximal tubule Na(+)-ATPase activity through the Gi protein-coupled receptor.