Cross Talk Between A₁ and A_2A Adenosine Receptors in the Hippocampus and Cortex of Young Adult and Old Rats

Abstract

Adenosine modulates synaptic transmission by acting on inhibitory A(1) and facilitatory A(2A) receptors, the densities of which are modified in aged animals. We investigated how A(2A) receptor activation influences A(1) receptor function and whether this interaction is modified in aged rats. In hippocampal and cortical nerve terminals from young adult (6 wk), but not old rats (24 mo), the A(2A) receptor agonist, 2-[4-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680; 30 nM) decreased the binding affinity of a selective A(1) receptor agonist, cyclopentyladenosine (CPA), an effect prevented by the A(2A) antagonist, (4-(2-[7-amino-2-(2-furyl (1,2,4)-triazolo(2,3-a (1,3,5)triazin-5-yl-aminoethyl)phenol (ZM 241385, 20 nM). This effect of CGS 21680 required intact nerve terminals and was also observed in the absence of Ca(2+). This A(2A)-induced "desensitization" of A(1) receptors was prevented by the protein kinase C inhibitor, chelerythrine (6 microM), and was not detected in the presence of the protein kinase C activator, phorbol-12,13-didecanoate (250 nM), which itself caused a reduction in binding affinity for CPA. The protein kinase A inhibitor, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (10 microM), and the protein kinase A activator, 8-Br-cAMP (1 mM), had no effects on the A(2A)-induced A(1) receptor desensitization. This A(2A)-induced A(1) receptor desensitization had a functional correlation because CGS 21680 (10 nM) attenuated by 40% the inhibition caused by CPA (10 nM) on CA1 area population spike amplitude in hippocampal slices. This A(2A)/A(1) interaction may explain the attenuation by adenosine deaminase (2 U/ml), which removes tonic A(1) inhibition, of the facilitatory effect of CGS 21680 on synaptic transmission. The requirement of tonic A(1) receptor activation for CGS 21680 to induce facilitation of synaptic transmission was reinforced by the observation that the A(1) receptor antagonist, 1, 3-dipropyl-8-cyclopentylxanthine (20 nM) prevented CGS 21680 (10 nM) facilitation of population spike amplitude. The present results show the ability of A(2A) receptors to control A(1) receptor function in a manner mediated by protein kinase C, but not protein kinase A, in young adult but not in aged rats.

Neuromuscular transmission modulation by adenosine upon aging

“…Nerve endings represent only a minor proportion of the tissue content in a nerve-muscle preparation, which precludes the use of receptor quantitative or semiquantitative assays, such as ligand binding studies or Western blot analysis. These approaches have been done in brain tissue, showing that the number of A 2A receptors, their affinity to ligands, and their coupling to G protein, is decreased in striatal membranes of aged rats (24 months) when compared with young adult animals (3 months) (Lopes et al, 1999). Also, the expression of A 2A messenger (m)RNA is decreased in striatum of aged rats (Schiffmann and Vanderhaeghen, 1993) and the excitatory effect of the A 2A receptor agonist, CGS 21680, on the spontaneous outflow of glutamate and aspartate in striatum was lost in aged rats (Corsi et al, 1999).…”

“…So, in what concerns A 2A receptor-mediated neuromodulation, the neuromuscular junction appears to behave more likely the striatum, in clear contrast with what happens in the hippocampus, where A 2A receptor-mediated excitatory tonus is increased upon aging (Cunha et al, 1995;Lopes et al, 1999). Interestingly, the motor inhibitory adenosinergic tone is increased in aged animals with respect to young animals (Popoli et al, 1998), which can be attributed, at least in part, to a loss of excitatory tonus at the neuromuscular junction (present report) and striatum (Corsi et al, 1999;Lopes et al, 1999;Schiffmann and Vanderhaeghen, 1993).…”

The adenosine kinase hypothesis of epileptogenesis

“…This occurs preferentially at high frequency stimulation (Cunha et al, 1996b), and extracellular degradation of synaptically released ATP to adenosine is not associated with the activation of inhibitory A 1 , but with activation of facilitatory A 2A receptors (Cunha et al, 1996a). Synaptic activation of A 2A receptors can subsequently downregulate A 1 receptors or its responses (Ciruela et al, 2006;Lopes et al, 1999). Thus, synaptic stimulation of A 2A receptors under high frequency conditions in epileptic circuits could lead to downregulation of A 1 receptors, a finding confirmed in chronic epilepsy (Ekonomou et al, 2000;Glass et al, 1996;Rebola et al, 2003).…”

Inhibition of spontaneous acetylcholine secretion by 2‐chloroadenosine as revealed by a protein kinase inhibitor at the mouse neuromuscular junction

“…This purine receptor may thus be desensitized, perhaps via phosphorylation, reducing the ability of CADO to activate the receptor. Although desensitization has not been observed for A 1 receptors on motor nerve endings in the frog (Silinsky, 1984) or the rat (Ginsborg & Hirst, 1972), it has been noted in rat brain preparations (Dixon et al, 1997;Lopes et al, 1999). This observation may indeed explain the lower e cacy of adenosine congeners on mouse motor nerve endings when compared to frog or rat.…”

“…In addition, cross talk between A 1 and A 2a receptors has been observed in rat brain whereby A 1 receptors are desensitized by A 2a receptors via the action of protein kinases (Dixon et al, 1997;Lopes et al, 1999). To investigate the possibility that A 2a receptor activation by endogenous adenosine mediates the reduced sensitivity to CADO, we examined the e ect of the highly selective A 2a antagonist ZM 241385 on spontaneous ACh release and on the action of 1 mM CADO.…”