Embrane potential of cells using the power of adenosine triphosphate (ATP) hydrolysis (Reinhard et al.,

Embrane potential of cells using the power of adenosine triphosphate (ATP) hydrolysis (Reinhard et al., 2013).Received Might 1, 2013; revised Oct. 15, 2013; accepted Oct. 16, 2013. Author contributions: M.M., R.A.C., and J.-F.C. created research; M.M. and E.A. performed study; J.-F.C. contributed unpublished reagents/analytic tools; M.M., E.A., P.A., R.A.C., and J.-F.C. analyzed information; M.M., R.A.C., and J.-F.C. wrote the paper. This function was supported by the Portuguese Foundation for Science and Technologies (PTDC/SAU-NSC/122254/ 2010), the National Institutes of Well being (Grant NS041083-07), and Defense Sophisticated Analysis Projects Agency (Grant 09-68-ESR-FP-010). M.M. and E.A. acknowledge their FCT/FSE (Fundacao para a Ciencia e a Tecnolgia/ ^ European Social Fund) fellowships (SFRH/BD/36289/2007, SFRH/BD/47824/2008). Correspondence β-lactam Chemical medchemexpress should be addressed to Rodrigo Cunha, CNC enter for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. E-mail: cunharod@gmail. DOI:ten.1523/JNEUROSCI.1828-13.2013 Copyright 2013 the authors 0270-6474/13/3318492-11 15.00/A functional NKA consists of a catalytic -subunit harboring the ATP-binding sites in addition to a smaller sized -subunit required for full enzymatic activity as well as functioning as an anchoring protein (Aperia, 2007). In the brain, 3 different -subunit isoforms are present inside a cell-specific manner: the low-affinity 1 is present in all cell kinds, the high-affinity two isoform is restricted to astrocytes, plus the high-affinity three isoform is expressed exclusively in neurons (Benarroch, 2011). As a result, it is not surprising that NKA activity and specifically the 2 isoform has emerged as a robust modulator of glutamate uptake in astrocytes, as heralded by the observations that (1) ATP depletion results in a reversal of glutamate uptake (κ Opioid Receptor/KOR Agonist Purity & Documentation Longuemare et al., 1999); (two) inhibitors of NKA, which include ouabain, impair glutamate transporter activity (Pellerin and Magistretti, 1997; Rose et al., 2009; Genda et al., 2011) and cause glutamate transporter clustering and redistribution (Nakagawa et al., 2008; Nguyen et al., 2010); and (three) the 2 subunit of NKA colocalizes and physically associates within the very same protein complex with glutamate transporters (Cholet et al., 2002; Rose et al., 2009; Genda et al., 2011). We’ve previously shown that adenosine, a classical and ubiquitous modulator of synaptic transmission (Fredholm et al., 2005), by activating astrocytic adenosine A2A receptors (A2ARs), controls the uptake of glutamate via a dual mechanism (Matos et al., 2012b): a long-term activation of A2AR triggers a cAMP/ protein kinase A-dependent lower with the expression of GLT-I and glutamate-aspartate transporter (GLAST) ahead of the reduction with the levels and activity of both transporters (Matos et al., 2012b), whereas the acute short-term activation of astrocytic A2ARs decreases the activity of glutamate transporters via an unknown mechanism that may well depend around the physical prox-Matos et al. A2A Receptor Controls Na /K -ATPaseJ. Neurosci., November 20, 2013 33(47):184928502 imity of A2ARs and GLT-I (Matos et al., 2012b). We’ve got now tackled the mechanism of A2AR-mediated inhibition of the astrocytic glutamate transport, which was identified to rely on a physical association and modulation by A2ARs of NKA- 2 in astrocytes. This delivers the very first demonstration that A2ARs handle ion homeostasis in astrocytes, paving the approach to realize the broad neuroprotective effect of A2AR antagonists in.