Tonic activation of A_2A adenosine receptors unmasks, and of A₁ receptors prevents, a facilitatory action of calcitonin gene‐related peptide in the rat hippocampus

Abstract

1 We investigated how manipulations of the degree of activation of adenosine A 1 and A 2A receptors in¯uences the action of the neuropeptide, calcitonin gene-related peptide (CGRP) on synaptic transmission in hippocampal slices. Field excitatory post-synaptic potentials (EPSPs) from the CA1 area were recorded. 2 When applied alone, CGRP (1 ± 30 nM) was without eect on ®eld EPSPs. However, CGRP (10 ± 30 nM) signi®cantly increased the ®eld EPSP slope when applied to hippocampal slices in the presence of the A 1 receptor antagonist, 1,3-dipropyl-8-cyclopenthyl xanthine (DPCPX, 10 nM), or in the presence of the A 2A adenosine receptor agonist CGS 21680 (10 nM). 3 The A 2A receptor antagonist, ZM 241385 (10 nM) as well as adenosine deaminase (ADA, 2 U ml 71 ), prevented the enhancement of ®eld EPSP slope caused by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this eect of CGRP requires the concomitant activation of A 2A adenosine receptors by endogenous adenosine. 4 The protein kinase-A inhibitors, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004, 10 mM) and adenosine 3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS, 50 mM), as well as the inhibitor of ATP-sensitive potassium (K ATP ) channels, glibenclamide (30 mM), prevented the facilitation of synaptic transmission caused by CGRP (30 nM) in the presence of DPCPX (10 nM), suggesting that this eect of CGRP involves both K ATP channels and protein kinase-A. 5 It is concluded that the ability of CGRP to facilitate synaptic transmission in the CA1 area of the hippocampus is under tight control by adenosine, with tonic A 1 receptor activation by endogenous adenosine`braking' the action of CGRP, and the A 2A receptors triggering this action.

Adenosine A1 Receptors and Microglial Cells Mediate CX3CL1-Induced Protection of Hippocampal Neurons Against Glu-Induced Death

“…Even the basal level of extracellular adenosine, and the corresponding tonic activation of ARs, can be responsible of the modulatory activity on synaptic transmission (see Fredholm et al, 2005). Furthermore, AR activation is necessary, as co-receptor requirement, either to permit or to enhance neuronal and glial response to purines (ATP, Gerwins and Fredholm, 1992;Färber et al, 2008), neuropeptides (VIP, Cunha-Reis et al, 2007; CGRP, Sebastião et al, 2000;GDNF, Gomes et al, 2009), cytokines (IL-6, Biber et al, 2008, growth and trophic factors (FGF, Flajolet et al, 2008;BDNF, Diógenes et al, 2004), and chemokines (CX3CL1, Lauro et al, 2008). Data reported in this study show that adenosine, in addition to its wellknown direct neuroprotective effect on neurons (see above) and indirect protective effects through CCL2, IL-6, and S-100b release by astrocytes (Schwaninger et al, 1997;Ciccarelli et al, 1999;Wittendorp et al, 2004), appears to enable the neurotrophic activity of different neurotrophins to occur, thereby extending the repertoire of actions for adenosine in brain homeostatic control.…”

The Role of Adenosine Signaling in Headache: A Review

“…The authors of this study ascribe this to adenosine’s regulation of the calcitonin gene-related peptide (CGRP), a neuropeptide that plays an integral role in migraine. An adenosine A 1 receptor agonist decreased the release of CGRP and trigeminal activity in cats while an A 2A receptor agonist facilitated CGRP’s effect on synaptic transmission [127,128]. Interestingly, electrical stimulation of the trigeminal ganglion increased mRNA and protein levels of both CGRP and adenosine A 2A receptors while decreasing mRNA and protein levels of adenosine A 1 receptors [129].…”

Modulation of Ca2+-currents by sequential and simultaneous activation of adenosine A1 and A2A receptors in striatal projection neurons

“…Interestingly, because A 2A -agonists had no significant action when applied alone (Fig. 2), it appeared as though A 1 -receptors occupation had to precede the activation of A 2A -receptors to observe their enhancing actions on Ca 2+ -currents [36,37,[43][44][45][46]. The reason why A 1 -receptors have to be activated first, in order to see the actions of A 2A -receptors, is under current research.…”