The Role of cGMP on Adenosine A1 Receptor-mediated Inhibition of Synaptic Transmission at the Hippocampus

Abstract

Both adenosine A1 receptor and cGMP inhibit synaptic transmission at the hippocampus and recently it was found that A1 receptor increased cGMP levels in hippocampus, but the role of cGMP on A1 receptor-mediated inhibition of synaptic transmission remains to be established. In the present work we investigated if blocking the NOS/sGC/cGMP/PKG pathway using nitric oxide synthase (NOS), protein kinase G (PKG), and soluble guanylyl cyclase (sGC) inhibitors modify the A1 receptor effect on synaptic transmission. Neurotransmission was evaluated by measuring the slope of field excitatory postsynaptic potentials (fEPSPs) evoked by electrical stimulation at hippocampal slices. N6-cyclopentyladenosine (CPA, 15 nM), a selective A1 receptor agonist, reversibly decreased the fEPSPs by 54 ± 5%. Incubation of the slices with an inhibitor of NOS (L-NAME, 200 μM) decreased the CPA effect on fEPSPs by 57 ± 9% in female rats. In males, ODQ (10 μM), an sGC inhibitor, decreased the CPA inhibitory effect on fEPSPs by 23 ± 6%, but only when adenosine deaminase (ADA,1 U/ml) was present; similar results were found in females, where ODQ decreased CPA-induced inhibition of fEPSP slope by 23 ± 7%. In male rats, the presence of the PKG inhibitor (KT5823, 1 nM) decreased the CPA effect by 45.0 ± 9%; similar results were obtained in females, where KT5823 caused a 32 ± 9% decrease on the CPA effect. In conclusion, the results suggest that the inhibitory action of adenosine A1 receptors on synaptic transmission at hippocampus is, in part, mediated by the NOS/sGC/cGMP/PKG pathway.

Adenosine receptors regulate gap junction coupling of the human cerebral microvascular endothelial cells hCMEC/D3 by Ca2+ influx through cyclic nucleotide‐gated channels

“…; Pinto et al . ). Therefore we analysed whether A 1 adenosine receptor‐ and cGMP‐dependent pathways may be involved in the 2‐PAA‐induced enhancement of the gap junction coupling.…”

“…; Pinto et al . ). The following findings, however, argue against the involvement of the A 1 adenosine receptor in the action of 2‐PAA on the gap junction coupling.…”

Adenosine A1 receptor-mediated protection of mouse hippocampal synaptic transmission against oxygen and/or glucose deprivation: a comparative study

“…Manipulating the duration of ischemia in hippocampal slices revealed sequential changes to synaptic transmission with varying levels of reversibility strongly influenced by A 1 Rs: 1) a rapid direct inhibition, 2) a slower onset of A 1 R-independent inhibition, 3) a transient reappearance of activity, and 4) an irreversible loss of transmission. The initial reversible inhibition is a well-known phenomenon caused by A 1 Rs (Latini et al 1999) that inhibit presynaptic voltage-dependent calcium channels (Gundlfinger et al 2007;Wu and Saggau 1994) in glutamatergic nerve terminals (Rebola et al 2005); the NOS-cGMP pathway also appears to be involved (Pinto et al 2016).…”

The Signaling Pathways Involved in the Anticonvulsive Effects of the Adenosine A1 Receptor

“…By blocking NOS, sGC and PKG, Cascalheira et al demonstrated that A 1 R-induced inhibition of neurotransmission in the CA1 region of hippocampal slices is partly mediated by the NO/cGMP pathway [ 181 , 182 ]. In cardiomyocytes, the activation of A 1 Rs stimulates NOS through activation of PLC and subsequent increase in Ca 2+ /calmodulin and PKC activity [ 183 ].…”