Adenosine, ‘pertussis-sensitive’ G-proteins, and K+ conductance in central mammalian neurones under energy deprivation

Abstract

There is a striking similarity between the effects of adenosine and of hypoxia or glucose depletion on membrane potential and conductance of hippocampal neurones in tissue slices of rat brain. Both induce a membrane hyperpolarization by an increase in potassium conductance. It seemed likely, therefore, that a rise in extracellular adenosine concentration during energy deprivation may link neuronal metabolism with membrane K ÷ conductance. To test this hypothesis, we have now investigated the effects of hypoxia/ glucose deprivation on hippocampal neurones from pertussis toxin-treated rats. In such slices adenosine had no effect on postsynaptic membrane potential and input resistance. Nevertheless, hypoxia or glucose depletion were as effective as in controls. These data provide evidence against adenosine as the main mediator between cell metabolism and potassium conductance.An early effect of energy deprivation in central mammalian neurones is an increase in membrane K + conductance. This has been observed during hypoxia [5][6][7]10] as well as during glucose depletion [14]. The controlling substance which links cellular metabolism and K ÷ conductance is still subject of discussion. It has been discussed that adenosine may be such a mediator [9] since adenosine induced an increase in neuronal K ÷ conductance [8,12,13] in electrophysiological studies on mammalian brain slices. Furthermore, the content of this purine increases in brain tissue under energy deprivation [3,4,9]. However, so far this hypothesis has not been adequately explored. In our experiments we made use of the knowledge that adenosine receptors are linked to K ÷ channels via pertussis toxin (PTX)-sensitive G-proteins [11]. Therefore, hypoxia and glucose deprivation were explored on PTX-treated rats.The experiments were performed on transverse slices (500/tm thick) or rat (250-300 g) hippocampus. The slices were kept totally immersed in an experimental chamber perfused with an oxygenated solution containing (in mM); NaCI 118, KCI

Action of adenosine receptor antagonists on hypoxia‐induced effects in the rat hippocampus in vitro

“…This suggests that cell hyperpolarization during hypoxia is not the result of G-protein-linked adenosine A1 receptors opening K+ channels. These results are in agreement with the studies of Leblond & Krnjevic (1989) who found that caffeine, a weak, non-selective adenosine antagonist (Bruns et al, 1986) did not attenuate hypoxia-induced hyperpolarization and Spuler & Grafe (1989) who found that pertussis toxin treatment (which abolished the hyperpolarization induced by application of exogenous adenosine) did not block the hyperpolarization during anoxia. The fall in evoked field potential amplitude seen during hypoxia is consistent with those of previous studies (e.g.…”

Adenosine A1 Receptor Inhibition of Glutamate Exocytosis and Protein Kinase C‐Mediated Decoupling

“…The adenosine A, receptor is expressed at high levels in the cerebral cortex, hippocampus, and cerebellum (Mahan et al,199 1). Identical or closely related receptors are present postsynaptically, where they lower cyclic AMP, activate K+ channels, and/or inhibit Ca2+ channels (for review, see Stone,I99 l), and presynaptically, where they inhibit, via a pertussis toxin-sensitive guanine nucleotide binding protein (G protein) (Dolphin and Prestwich, 1985;Spuler and Grafe, 1989;Stone, 1991), the evoked release of a number of transmitters, including glutamate (Dolphin and Archer, 1983;Dolphin and Prestwich, 1985;Prestwich et al, 1987;Burke and Nadler, 1988;Dunwiddie et al, 1990;Poli et al, 1991), but notably excluding y-aminobutyric acid (GABA) (Yoon and Rothman,199 1).…”

Effects of transient oxygen-glucose deprivation on G-proteins and G-protein-coupled receptors in rat CA3 pyramidal cellsin vitro

“…Indeed, Zhu & Krnjevic (1997) found that in CA1 pyramidal cells the hypoxic outward current was significantly reduced in the presence of 8‐SPT, a selective adenosine A1 receptor antagonist. On the other hand, the hyperpolarization induced by hypoxia or glucose deprivation was preserved in hippocampal slices in which the adenosine response was abolished by pretreatment with PTX (Spuler & Grafe 1989). Similarly, we observed no significant difference in the OGD‐induced outward current in controls versus cells treated with PTX or the adenosine receptor antagonist DPSPX.…”