Inhibition of Na⁺, K⁺‐ATPase activity in rat striatum by the metabolites accumulated in Lesch–Nyhan disease

Abstract

In the present study, we investigated the in vitro effect of hypoxanthine, xanthine and uric acid, metabolites accumulating in tissue of patients with Lesch-Nyhan disease, on Na(+), K(+)-ATPase activity in striatum of neonate rats. Results showed that all compounds significantly inhibited Na(+), K(+)-ATPase activity. We also studied the kinetics of the inhibition of Na(+), K(+)-ATPase activity caused by hypoxanthine. The apparent K(m) and V(max) of Na(+), K(+)-ATPase activity for ATP as the substrate and hypoxanthine as the inhibitor were 0.97 mM and 0.69 nmol inorganic phosphate (Pi) released per min per mg of protein, respectively. K(i)-value was 1.9 microM, and the inhibition was of the non-competitive type. We also observed that the inhibitory effects of hypoxanthine, xanthine and uric acid probably occur through the same mechanism, suggesting a common binding site for these oxypurines on Na(+), K(+)-ATPase. Therefore, it is conceivable that inhibition of brain Na(+), K(+)-ATPase activity may be involved at least in part in the neuronal dysfunction characteristic of patients with Lesch-Nyhan disease.

Uric Acid Inhibits Placental System A Amino Acid Uptake

“…Additionally, uncoupling of nitric oxide synthase and subsequent generation of superoxide mediates inhibition of the Na + –K + -ATPase pump in cardiac myocytes [41]. Interestingly, uric acid treatment, at concentrations similar to those used in this study, reduced Na + –K + -ATPase pump activity by 50% in rat striatum [42]. The results of this study, along with the evidence of altered Na + –K + -ATPase activity in the presence of increased free radicals, suggest that the inhibitory effects of uric acid-induced redox signaling on System A transport activity may be the result of inadequate establishment of intracellular sodium gradients.…”

Effect of uric acid on hypertension progression in spontaneously hypertensive rats

“…The enzyme activity is not altered in proximal tubules of adult SHR animals (Hinojos and Doris 2004). Uric acid inhibits the enzyme from rat striatum synaptic membranes (Bavaresco et al 2004). According to our results, UA inhibited the Na + /K + /ATPase from kidney cortex by 35% in the SHR-UA group.…”

Na,K-ATPase Activity Regulates AMPA Receptor Turnover through Proteasome-Mediated Proteolysis

“…Reduced NKA activity has also been observed during aging and in aging-related neurodegenerative diseases such as Alzheimer's disease (Bahr et al, 1992; Nicoletti et al, 1995; Ossowska et al, 2001). Furthermore, dysfunction of synaptic NKA has also been implicated in certain metabolic disorders including maple syrup urine disease (Wajner et al, 2007), isovaleric acidemia (Ribeiro et al, 2007) and Lesch-Nyhan disease (Bavaresco et al, 2004). It is of interest to investigate whether the NKA-AMPAR crosstalk plays any roles in the neuronal dysfunctions present in these diseases.…”