Adenosine A2A receptor facilitation of synaptic transmission in the CA1 area of the rat hippocampus requires protein kinase C but not protein kinase A activation

Transducing system operated by adenosine A2A receptors to facilitate acetylcholine release in the rat hippocampus

“…Also, in aged animals, the control of hippocampal glutamatergic transmission is not significantly changed by blockade of adenosine A 1 receptors ) whereas in young adult animals, the adenosine A 2A receptor-mediated facilitation of synaptic transmission is strictly dependent on tonic adenosine A 1 receptor activation (Lopes et al, 2002). Interestingly, whereas adenosine A 2A receptor facilitation of hippocampal excitatory synaptic inhibition is mediated by protein kinase C in young adult animals (Cunha and Ribeiro, 2000b), it mostly involves activation of protein kinase A in aged animals ). Thus, it appears that when adenosine A 2A receptor-mediated effects involve protein kinase A, then these effects become independent of adenosine A 1 receptor function, as was presently confirmed for the adenosine A 2A receptor-mediated facilitation of the evoked release of acetylcholine from hippocampal nerve terminals.…”

“…The presence of adenosine A 2A receptors in the hippocampus has been confirmed using molecular biology studies, like polymerase chain reaction (PCR), in situ hybridization (Cunha et al, 1994b) and Northern blot analysis (Peterfreund et al, 1996), but binding studies have revealed an atypical binding pattern (Cunha et al, 1996) and G protein coupling (Cunha et al, 1999) of these putative adenosine A 2A receptors. Some functional peculiarities of the facilitatory effects of the prototypical adenosine A 2A receptor agonist, CGS 21680 (Fredholm et al, 1994), include the strict dependency on co-activation of adenosine A 1 receptors in the control of glutamate release (Lopes et al, 2002), the atypical pharmacology in the control of GABA release (Cunha and Ribeiro, 2000a) and the coupling to protein kinase C in the control of excitatory synaptic transmission (Cunha and Ribeiro, 2000b;Lopes et al, 2002). Thus, none of the neurotransmitter systems controlled by putative adenosine A 2A receptors has yet proven to obey to a clear and typical adenosine A 2A receptor pharmacology and to be coupled to the postulated cAMP/protein kinase A transducing pathway (Fredholm et al, 1994).…”

Adenosine A2A Receptor Facilitates Calcium-Dependent Protein Secretion through the Activation of Protein Kinase A and Phosphatidylinositol-3 Kinase in PC12 Cells

“…Although activation of A 2A -R in general facilitates calcium-dependent exocytosis of synaptic vesicles (with a few exceptions) (Sebastiao and Ribeiro, 2000;Cunha and Ribeiro, 2000a;Mori and Shindou, 2003;Okada et al, 2001;Marchi et al, 2002;Kirk and Richardson, 1994;Kurokawa et al, 1994;Cunha and Ribeiro, 2000b), it has not been investigated so far whether A 2A -R activation also facilitates exocytosis of dense-core secretary vesicles. We established a stable cell line of PC12 cells expressing NPY-Venus, a fusion protein between NPY and a yellow fluorescence protein variant relatively resistant to low pH (Venus), which has been shown to be efficiently targeted to dense-core vesicles (Nagai et al, 2002).…”

“…However, it is still largely unknown how A 2A -R modulates cellular functions. Recent studies have shown that activation of A2A-R facilitates calcium-dependent secretion of various neurotransmitters such as GABA, serotonin and glutamate in hippocampal and laterodorsal tegmental cells (Sebastiao and Ribeiro, 2000;Cunha and Ribeiro, 2000a;Mori and Shindou, 2003;Okada et al, 2001;Marchi et al, 2002;Cunha and Ribeiro, 2000b). These results tempted us to dissect the downstream signaling pathways of A 2A -R in regulation of calcium-dependent secretion.…”

Local Glutamate Level Dictates Adenosine A2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury

“…The cAMP-PKA pathway has been identified as the main signaling cascade responsible for A 2A R-mediated inhibition of acute inflammation (Cronstein, 1994;Haskó and Cronstein, 2004;Sitkovsky et al, 2004;Fredholm et al, 2007). However, A 2A R activation can signal through cAMP-PKA independent pathways as well (Fredholm et al, 2007), including PKC (Lai et al, 1997;Cunha and Ribeiro, 2000;Pinto-Duarte et al, 2005), MAPK (mitogen-activated protein kinase) (Cheng et al, 2002;Schulte and Fredholm, 2003;Gianfriddo et al, 2004;Melani et al, 2006), ␤-arrestin (Khoa et al, 2006), and even Src-TrkA pathway (Malek et al, 1999). In addition, recent studies show that the C terminus of the A 2A R binds to several interacting proteins [actinin, ARNO (ARF nucleotide binding site opener), Usp4, and TRAX (Translin-associated factor X)] and might mediate the G-protein-independent function of A 2A Rs (for review, see Fredholm et al, 2007).…”