The Role of CGMP on Adenosine A 1 Receptor-mediated Inhibition of Synaptic Transmission at the Hippocampus

Overview

Journal Front Pharmacol

Date 2016 May 6

PMID 27148059

Citations 4

Authors

Isa Pinto

Andre Serpa

Ana M Sebastiao

Jose F Cascalheira

Affiliations

Soon will be listed here.

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.

Citing Articles

Development of therapeutic supplement using roasted-cashew-nut to protect cerebral vasoconstriction injury triggered by mixture of petroleum hydrocarbons in the hypothalamus and hippocampus of rat model.

Akintunde J, Akomolafe V, Ugbaja R, Olude A, Folayan A Toxicol Rep. 2025; 14:101943.

PMID: 39996038 PMC: 11848775. DOI: 10.1016/j.toxrep.2025.101943.

Hypoxia Depresses Synaptic Transmission in the Primary Motor Cortex of the Infant Rat-Role of Adenosine A Receptors and Nitric Oxide.

Zironi I, Aicardi G Biomedicines. 2022; 10(11).

PMID: 36359395 PMC: 9687150. DOI: 10.3390/biomedicines10112875.

The Signaling Pathways Involved in the Anticonvulsive Effects of the Adenosine A Receptor.

Spanoghe J, Larsen L, Craey E, Manzella S, Van Dycke A, Boon P Int J Mol Sci. 2021; 22(1).

PMID: 33396826 PMC: 7794785. DOI: 10.3390/ijms22010320.

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

Kawamura Jr M, Ruskin D, Masino S J Neurophysiol. 2019; 122(2):721-728.

PMID: 31242045 PMC: 6734406. DOI: 10.1152/jn.00813.2018.

Adenosine receptors regulate gap junction coupling of the human cerebral microvascular endothelial cells hCMEC/D3 by Ca influx through cyclic nucleotide-gated channels.

Bader A, Bintig W, Begandt D, Klett A, Siller I, Gregor C J Physiol. 2017; 595(8):2497-2517.

PMID: 28075020 PMC: 5390872. DOI: 10.1113/JP273150.

References

Lucas K, Pitari G, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S . Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev. 2000; 52(3):375-414. View

Cascalheira J, Sebastiao A, Alexandre Ribeiro J . Pertussis toxin-sensitive G proteins mediate the inhibition of basal phosphoinositide metabolism caused by adenosine A1 receptors in rat hippocampal slices. Neurochem Res. 2003; 27(12):1707-11. DOI: 10.1023/a:1021603614916. View

Sequeira S, Carvalho A, Carvalho C . Both protein kinase G dependent and independent mechanisms are involved in the modulation of glutamate release by nitric oxide in rat hippocampal nerve terminals. Neurosci Lett. 1999; 261(1-2):29-32. DOI: 10.1016/s0304-3940(98)01002-7. View

Serpa A, Ribeiro J, Sebastiao A . Cannabinoid CB(1) and adenosine A(1) receptors independently inhibit hippocampal synaptic transmission. Eur J Pharmacol. 2009; 623(1-3):41-6. DOI: 10.1016/j.ejphar.2009.09.020. View

Boulton C, Southam E, Garthwaite J . Nitric oxide-dependent long-term potentiation is blocked by a specific inhibitor of soluble guanylyl cyclase. Neuroscience. 1995; 69(3):699-703. DOI: 10.1016/0306-4522(95)00349-n. View

Orio M, Kunz A, Kawano T, Anrather J, Zhou P, Iadecola C . Lipopolysaccharide induces early tolerance to excitotoxicity via nitric oxide and cGMP. Stroke. 2007; 38(10):2812-7. DOI: 10.1161/STROKEAHA.107.486837. View

Franco R, Ciruela F, Casado V, Cortes A, Canela E, Mallol J . Partners for adenosine A1 receptors. J Mol Neurosci. 2005; 26(2-3):221-32. DOI: 10.1385/JMN:26:2-3:221. View

Lopes L, Cunha R, Ribeiro J . Cross talk between A(1) and A(2A) adenosine receptors in the hippocampus and cortex of young adult and old rats. J Neurophysiol. 1999; 82(6):3196-203. DOI: 10.1152/jn.1999.82.6.3196. View

Lei S, Jackson M, Jia Z, Roder J, Bai D, Orser B . Cyclic GMP-dependent feedback inhibition of AMPA receptors is independent of PKG. Nat Neurosci. 2000; 3(6):559-65. DOI: 10.1038/75729. View

10.

Santschi L, Zhang X, Stanton P . Activation of receptors negatively coupled to adenylate cyclase is required for induction of long-term synaptic depression at Schaffer collateral-CA1 synapses. J Neurobiol. 2005; 66(3):205-19. DOI: 10.1002/neu.20213. View

11.

Fischer H, Prast H, Philippu A . Adenosine release in the ventral striatum of the rat is modulated by endogenous nitric oxide. Eur J Pharmacol. 1995; 275(3):R5-6. DOI: 10.1016/0014-2999(95)00097-5. View

12.

Saransaari P, Oja S . Involvement of nitric oxide in adenosine release in the developing and adult mouse hippocampus. Neurochem Res. 2004; 29(1):219-25. DOI: 10.1023/b:nere.0000010451.81201.f5. View

13.

Boulton C, Irving A, Southam E, Potier B, Garthwaite J, Collingridge G . The nitric oxide--cyclic GMP pathway and synaptic depression in rat hippocampal slices. Eur J Neurosci. 1994; 6(10):1528-35. DOI: 10.1111/j.1460-9568.1994.tb00543.x. View

14.

Kleppisch T . Phosphodiesterases in the central nervous system. Handb Exp Pharmacol. 2008; (191):71-92. DOI: 10.1007/978-3-540-68964-5_5. View

15.

Cascalheira J, Sebastiao A . Adenosine A1 receptor activation inhibits basal accumulation of inositol phosphates in rat hippocampus. Pharmacol Toxicol. 1998; 82(4):189-92. DOI: 10.1111/j.1600-0773.1998.tb01423.x. View

16.

Dias R, Rombo D, Ribeiro J, Henley J, Sebastiao A . Adenosine: setting the stage for plasticity. Trends Neurosci. 2013; 36(4):248-57. DOI: 10.1016/j.tins.2012.12.003. View

17.

Fredholm B, Dunwiddie T . How does adenosine inhibit transmitter release?. Trends Pharmacol Sci. 1988; 9(4):130-4. DOI: 10.1016/0165-6147(88)90194-0. View

18.

Potter B, Galione A, Stanton P . Induction of hippocampal LTD requires nitric-oxide-stimulated PKG activity and Ca2+ release from cyclic ADP-ribose-sensitive stores. J Neurophysiol. 1999; 82(3):1569-76. DOI: 10.1152/jn.1999.82.3.1569. View

19.

Prast H, Philippu A . Nitric oxide as modulator of neuronal function. Prog Neurobiol. 2001; 64(1):51-68. DOI: 10.1016/s0301-0082(00)00044-7. View

20.

de Mendonca A, Ribeiro J . Long-term potentiation observed upon blockade of adenosine A1 receptors in rat hippocampus is N-methyl-D-aspartate receptor-dependent. Neurosci Lett. 2000; 291(2):81-4. DOI: 10.1016/s0304-3940(00)01391-4. View