Abstract
Adenosine-induced modulation of neuromuscular transmission in young (3–4-week-old) rats was evaluated. Inhibition of adenosine kinase with iodotubercidin (ITU; 10 μM), which is known to induce adenosine release, enhanced the amplitude of evoked end-plate potentials (EPPs) recorded from innervated diaphragm muscle fibers. This facilitatory effect was transformed into an inhibitory one upon blockade of adenosine A2A receptors with 4-(2-[7-amino-2-(2-furly)[1,2,4]triazolo[2,3-a][1,3,5]triazin5ylamino] ethyl) phenol (ZM 241385) (50 nM); further blockade of adenosine A1 receptors with the selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 nM) abolished that inhibition. Adenosine or 2-chloroadenosine (CADO), at submicromolar concentrations, increased the amplitude and the quantal content of EPPs, whereas at low micromolar concentrations they decreased EPP amplitude. Blockade of A1 receptors with DPCPX (10 nM) prevented both excitatory and inhibitory effects, whereas blockade of A2A receptors with ZM241385 (50 nM) prevented only the excitatory effects. DPCPX and ZM241385 also prevented the excitatory effect of the selective A2A receptor agonist 2-[p-(2-carboxyethyl) phenethylamino]-5′-N-ethylcarboxamido adenosine hydrochloride (CGS 21680; 10 nM). CADO (30 nM) also increased neuromuscular transmission in adult (12–16-week-old) rats. It is suggested that at the motor nerve endings, low extracellular concentrations of adenosine activate both A2A and A1 receptors, but activation of A2A receptors predominates over A1 receptors; the activity of A2A receptors might, however, require coactivation of A1 receptors. This facilitatory action of low concentrations of extracellular adenosine upon acetylcholine release may be particularly relevant at developing neuromuscular junctions, where subtle changes in synaptic levels of acetylcholine might influence synaptic stabilization.
Footnotes
-
This work was supported by Fundação do Ministério de Ciência e Tecnologia de Portugal and European Union [Grant NEREPLAS, COST B30]. P.A.P. is the recipient of a Fundação do Ministério de Ciência e Tecnologia de Portugal fellowship [Grant SFRH/BD/28073/2006].
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.157255
-
ABBREVIATIONS:
- q.c.
- quantal content
- EPP
- evoked end-plate potential
- NMJ
- neuromuscular junction
- A1R
- adenosine A1 receptor
- A2AR
- adenosine A2A receptor
- AR
- adenosine receptor
- AK
- adenosine kinase
- NMT
- neuromuscular transmission
- AKI
- adenosine kinase inhibitor
- ITU
- 5′-iodotubericidin
- CADO
- 2-chloroadenosine
- MEPP
- miniature end-plate potential
- ADA
- adenosine deaminase
- DPCPX
- 1,3-dipropyl-8-cyclopentylxanthine
- AICAR
- 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside
- ZM 241385
- 4-(2-[7-amino-2-(2-furly)[1,2,4]triazolo[2,3-a][1,3,5]triazin5ylamino] ethyl) phenol
- CGS 21680
- 2-[p-(2-carboxyethyl) phenethylamino]-5′-N-ethylcarboxamido adenosine hydrochloride
- AMPK
- AMP-activated protein kinase
- ADO
- adenosine.
- Received June 8, 2009.
- Accepted September 28, 2009.
- © 2010 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|