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Glutamate modulates sodium‐potassium‐ATPase through cyclic GMP and cyclic GMP‐dependent protein kinase in rat striatum

Excessive excitatory action of glutamate and nitric oxide (NO) has been implicated in degeneration of striatal neurons. Evidence had been provided that Na+K+‐ATPase might be involved in this process. Here we investigated whether glutamate‐regulated messengers, such as NO and cyclic GMP, could modulate the activity of membrane Na+K+‐ATPase. Our results demonstrated that NO donors sodium nitroprusside (SNP at 30 and 300 μM) and S‐nitroso‐N‐acetylpenicillamine (SNAP at 200 μM) increased α2,3Na+K+‐ATPase activity which was blocked by the NO chelator, haemoglobin and was independent of [Na+]. This regulation was associated with cGMP synthesis and mimicked by glutamate (300 μM) and 8‐Br‐cyclic GMP (4 mM). 8‐Br‐cGMP‐induced stimulation of Na+K+‐ATPase activity could be blocked by KT5823 (an inhibitor of cGMP‐dependent protein kinase, PKG), but not by KT5720 (an inhibitor of cAMP‐dependent protein kinase, PKA). N‐Methyl‐D‐aspartate (NMDA) receptors appeared to be involved in the effect of glutamate, since MK‐801 (NMDA receptor antagonist) produced a partial reduction in glutamate‐induced activation of the enzyme. MK‐801 was not synergistic to L‐NAME (NOS inhibitor), suggesting that glutamate stimulates the NMDA‐NOS pathway to activate α2,3 Na+K+‐ATPase in rat striatum. This regulation was associated with cyclic GMP (but not cyclic AMP) synthesis. These data indicate the existence, in vitro, of a regulatory pathway by which glutamate, acting through NO and cGMP, can cause alterations in striatal α2,3 Na+K+‐ATPase activity. Copyright © 2004 John Wiley & Sons, Ltd.