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  • Among the enzymes involved in adenosine metabolism


    Among the enzymes involved in adenosine metabolism, adenosine kinase plays an important role in regulating formation and release of endogenous adenosine in cardiomyocytes as well as vascular endothelial cells Decking et al., 1997, Kowaluk et al., 1998, Smolenski et al., 1994. Inhibition of adenosine kinase increases the extracellular adenosine level by increasing intracellular adenosine concentration and thereby increasing net release of adenosine from cells Decking et al., 1997, Gorman et al., 1997. In fact, several studies have shown that adenosine kinase inhibitors have potent anti-inflammatory effects in animal models of inflammation Bouma et al., 1997b, Cronstein et al., 1995. In rat models of septic shock, in vivo administration of an adenosine kinase inhibitor, GP-1-515 significantly reduced mortality, and this beneficial effect was attributed to A2 adenosine receptor-mediated endogenous adenosine actions, such as decreased pulmonary neutrophil accumulation and decreased plasma levels of tumor necrosis factor-α (Firestein et al., 1994). Other studies also demonstrated that GP-1-515 reduced neutrophil degranulation (Bouma et al., 1997a), and neutrophil transmigration and vascular leakage in a skin model of inflammation in vivo (Rosengren et al., 1995). Accordingly, adenosine kinase is thought to play an important role in regulating endogenous adenosine release, which in turn regulates a vast array of cellular functions Bouma et al., 1997b, Mullane and Bullough, 1995. Hence, understanding the biochemical mechanisms involved in the regulation of adenosine kinase will be important in the development of therapeutic drugs targeting the adenosine system. We tested the hypothesis that FK506 induces adenosine release from cultured endothelial cells via inhibition of adenosine kinase activity. In the present study, we chose endothelial cells as a model system because recent studies suggest that the vascular endothelium is a potentially important source and target of endogenous adenosine (Mullane and Bullough, 1995).
    Materials and methods
    Adenosine kinase, the key enzyme in adenosine metabolism Astrocytes serve as a key regulator of adenosine tone in the eph receptor through adenosine (ADK) mediated metabolic clearance (Boison, 2008, Boison et al., 2010). As a consequence, an increase in astrogliosis, as observed across multiple disease processes including epilepsy (Sofroniew and Vinters, 2010) and Alzheimer’s disease (Cagnin et al., 2001, Nagele et al., 2004), has profound effects on extracellular adenosine levels and adenosine mediated signaling (Boison, 2008). The significance of pathological changes in adenosine tone become readily apparent in light of adenosine’s potent anticonvulsant (Dragunow, 1986) and neuroprotective (Dragunow and Faull, 1988) actions that are mediated by the G protein-coupled adenosine A1 receptor (A1R) (Fredholm et al., 2005b, Fredholm et al., 2005a, Fedele et al., 2006, Boison et al., 2010). Independent of the adenosine tone, excessive network activity causes an adenosine surge that induces a state of synaptic depression and inhibits excitatory neurons (Dunwiddie, 1980, Mitchell et al., 1993, Manzoni et al., 1994), which in the context of seizures or epilepsy is anticonvulsant (Dragunow, 1991, Gouder et al., 2003). Therefore, adenosine augmentation strategies, in particular those restricted to a hyperexcitable brain area, hold promise as a rational approach for epilepsy therapy (Boison, 2009). Both astrocytes and neurons have been established as a source for extracellular adenosine (Fig. 1). In regards to astrocytes, high frequency stimulation of the CA1 pyramidal neurons induces a Ca2+ mediated release of ATP from astrocytes (Cotrina et al., 1998, Zhang et al., 2003, Pascual et al., 2005) through either vesicular transport (Pascual et al., 2005) or hemichannels (Kang et al., 2008). Once in the synaptic cleft ATP is rapidly converted to adenosine by a series of ectonucleotidases (Zimmermann, 2000). Recently, neurons have also been implicated as a source for synaptic adenosine, whereby stimulation of postsynaptic CA1 neurons evokes a release of adenosine that suppresses excitatory transmission (Lovatt et al., 2012). Adenosine is removed from the extracellular space by equilibrative (Baldwin et al., 2004) and concentrative (Gray et al., 2004) nucleoside transporters, which are expressed in both astrocytes and neurons (Guillen-Gomez et al., 2004, Peng et al., 2005, Alanko et al., 2006). Importantly, expression of ADK in astrocytes (Studer et al., 2006) allows the influx and metabolic clearance of adenosine (Boison et al., 2010), whereas the lack of ADK in neurons permits those cells to release adenosine directly (Lovatt et al., 2012). Within the astrocyte cytoplasm adenosine is rapidly phosphorylated by ADK, which converts the ribonucleoside into 5′-adenosine monophosphate (AMP) (Mimouni et al., 1994). As a consequence, neuropathological changes that cause astrogliosis and an associated increase in ADK, as observed in epilepsy, can reduce synaptic adenosine levels thereby increasing network excitability and the propensity for ictogenesis (Fedele et al., 2005, Etherington et al., 2009).