Abstract. Dopamine (DA) receptors, which belong to the G protein-coupled receptor family, are the target of ~50% of all modern medicinal drugs and constitute a large and diverse class of proteins whose primary function is to transduce extracellular stimuli into intracellular signals. Na + /K + -ATPase (NKA) is ubiquitous and crucial for the maintenance of intracellular ion homeostasis and excitability. Furthermore, it plays a critical role in diverse effects, including clinical cardiotonic and cardioprotective effects, ischemic preconditioning in the brain, natriuresis, lung edema clearance and other processes. NKA regulation is of physiological and pharmacological importance and has species-and tissue-specific variations. The activation of DA receptors regulates NKA expression/activity and trafficking in various tissues and cells, for example in the kidney, lung, intestine, brain, non-pigmented ciliary epithelium and the vascular bed. DA receptor-mediated regulation of NKA mediates a diverse range of cellular responses and includes endocytosis/exocytosis, phosphorylation/dephosphorylation of the α subunit of NKA and multiple signaling pathways, including phosphatidylinositol (PI)-phospholipase C/protein kinase (PK) C, cAMP/PKA, PI3K, adaptor protein 2, tyrosine phosphatase and mitogen-activated protein kinase/extracellular signal-regulated protein kinase. Furthermore, in brain and HEK293T cells, D 1 and D 2 receptors exist in a complex with NKA. Among D 1 and D 2 receptors and NKA, regulations are reciprocal, which leads to crosstalk between DA receptors and NKA. In the present study, the current understanding of signaling mechanisms responsible for the crosstalk between DA receptors and NKA, as well as with specific consequent functions, is reviewed.

Previous studies have shown that intermittent hypobaric hypoxia (IH) preconditioning protected neurons survival from brain ischemia. However, the mechanism remains to be elucidated. The present study explored the role of nitric oxide (NO) in the process by measuring the expression of NO synthase (NOS) and NO levels. Male Wistar rats (100) were randomly assigned into four groups: sham group, IH + sham group, ischemia group and IH + ischemia group. Rats for IH preconditioning were exposed to hypobaric hypoxia mimicking 5000 m high-altitude (P = 404 mmHg, PO = 84 mmHg) 6 h/day, once daily for 28 days. Global brain ischemia was established by four-vessel occlusion that has been created by Pulsinelli. Rats were sacrificed at 7th day after the ischemia for neuropathological evaluation by thionin stain. In addition, the expression of neuronal NOS (nNOS), inducible NOS (iNOS), and NO content in the hippocampal CA1 subfield were measured at 2nd day and 7th day after the ischemia. Results revealed that global brain ischemia engendered delayed neuronal death (DND), both nNOS and iNOS expression up-regulated, and NO content increased in the hippocampal CA1 subfield. IH preconditioning reduced neuronal injury induced by the ischemia, and prevented the up-regulation of NOS expression and NO production. In addition, L-NAME + ischemia group was designed to detect whether depressing NO production could alleviate the DND. Pre-administration of L-NAME alleviated DND induced by the ischemia. These results suggest that IH preconditioning plays a protective role by inhibiting the over expression of NOS and NO content after brain ischemia.

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Glutamate excitotoxicity in cerebral ischemia/reperfusion is an important cause of neurological damage. The aim of this study was to investigate the mechanism of Na+, K+-ATPase (NKA) involved in l ow concentration of ouabain (Oua, activating NKA)-induced protection of rat cerebral ischemia-reperfusion injury. The 2,3,5triphenyltetrazolium chloride (TTC) staining and neurological deficit scores (NDS) were performed to evaluate rat cerebral injury degree respectively at 2 h, 6 h, 1 d and 3 d after reperfusion of middle cerebral artery occlusion (MCAO) 2 h in rats. NKA a1/a2 subunits and glutamate transporter-1 (GLT-1) protein expression were investigated by Western blotting. The cerebral infarct volume ratio were evidently decreased in Oua group vs MCAO/R group at 1 d and 3 d after reperfusion of 2 h MCAO in rats (*p ＜ 0.05 ). Moreover, NDS were not significantly different (p ＞ 0.05 ). NKA a1 was decreased at 6 h and 1 d after reperfusion of 2 h MCAO in rats, and was improved in Oua group. However, NKA a1 and a2 were increased at 3 d after reperfusion of 2 h MCAO in rats, and was decreased in Oua group. GLT-1 was decreased at 6 h, 1 d and 3 d after reperfusion of 2 h MCAO in rats, and was improved in Oua group. These data indicated that l ow concentration of Oua could improve MCAO/R injury through probably changing NKA a1/a2 and GLT-1 protein expression, then increasing GLT-1 function and promoting Glu transport and absorption, which could be useful to determine potential therapeutic strategies for patients with stroke. Low concentration of Oua improved rat MCAO/ R injury via NKA a1/a2 and GLT-1.

Glutamate excitotoxicity is responsible for neuronal death in acute neurological disorders, including stroke, trauma and neurodegenerative diseases. Astrocytes are the main cells for the removal of glutamate in the synaptic cleft and may affect the tolerance of neurons to the glutamate excitotoxicity. Therefore, the present study aimed to investigate the tolerance of rat cortical neurons to glutamate excitotoxicity in the presence and absence of astrocytes. Rat cortical neurons in the presence or absence of astrocytes were exposed to different concentrations of glutamate (10–2,000 µM) and 10 µM glycine for different incubation periods. After 24 h, the Cell Counting kit-8 (CCK-8) assay was used to measure the cytotoxicity to neurons in the presence or absence of astrocytes. According to the results, in the absence of astrocytes, glutamate induced a concentration-dependent decrease of neuronal survival rate compared with the control rat cortical neurons, and the neurotoxic half-maximal inhibitory concentration (IC 50 ) at 15, 30 and 60 min was 364.5, 258.5 and 138.3 µM, respectively. Furthermore, in the presence of astrocytes, glutamate induced a concentration-dependent decrease of neuronal survival rate compared with the control rat cortical neurons, and the neurotoxic IC 50 at 15, 30 and 60 min was 1,935, 932.8 and 789.3 µM, respectively. However, astrocytic toxicity was not observed when the rat cortical astrocytes alone were exposed to different concentrations of glutamate (500, 1,000 and 2,000 µM) for 6, 12 and 24 h. In conclusion, the glutamate-induced neurotoxic IC 50 values at 15, 30 and 60 min were respectively higher in the presence of astrocytes as compared with those in the absence of astrocytes, suggesting that astrocytes can protect against rat cortical neuronal acute damage induced by glutamate.