Release and effects of ATP and its derivatives at cholinergic synapses

Abstract

ATP is released from many central and peripheral terminals in a rapid, synchronous manner. It can act both as a neurotransmitter substance and as a neuromodulator in conjunction with a primary neurotransmitter. We begin this perspective by reviewing the evidence for the quantal release of ATP together with acetylcholine (ACh) from motor nerve endings. Next, we discuss the inhibitory effects of adenosine derivatives on presynaptic and postsynaptic membranes at cholinergic synapses. With regard to the presynaptic effects of adenosine, after hydrolysis to adenosine ATP is the mediator of skeletal neuromuscular depression at low frequencies of stimulation. The evidence confirming the suggestion that this inhibitory effect of adenosine at motor nerve endings is mediated downstream of calcium entry is presented. Finally, the data showing the mutually occlusive effects of ATP and ACh at cholinoceptive neurons are summarized and discussed. Drug Dev. Res. 52:22-33, 2001 OVERVIEWATP is released as a neurotransmitter proper in the peripheral and central nervous systems [Edwards et al., 1992;Silinsky and Gerzanich, 1993;Evans et al., 1992;Galligan and Bertrand, 1994; see Silinsky et al., 1998, for review]. ATP also is released together with neurotransmitter substances [Silinsky and Hubbard, 1973;Silinsky, 1975] and, once it is in the extracellular domain, can exert both presynaptic and postsynaptic actions on the release or effects of the neurotransmitter [for reviews see Silinsky et al., 1998;Burnstock and Williams, 2000]. This review focuses on the release of ATP and the effects of released ATP derivatives at presynaptic membranes strategically designed for the release of acetylcholine (ACh) and at postsynaptic membranes that possess nicotinic receptors for ACh. We begin by describing the detection of the release of ATP in response to discrete, temporally isolated nerve impulses from motor nerve endings together with the neurotransmitter ACh. We then review the evidence that this ATP release, after hydrolysis to adenosine, mediates presynaptic neuromuscular depression. Finally, we review the data showing the mutually occlusive postsynaptic effects of P2X ATP receptor activation and nicotinic receptor agonists. DETECTION OF ATP RELEASE FROM NERVE ENDINGS USING BIOCHEMICAL METHODSIn early studies of the co-release of ATP and ACh, the bathing fluid from stimulated preparations was removed and assayed for ATP by the luciferin-luciferase method [Silinsky and Hubbard, 1973;Silinsky, 1975]. These results suggested an intimate stoichiometry between the release of ATP and its hydrolysis products and the neurotransmitter ACh. ACh release was detected electrophysiologically by measuring evoked synaptic responses (end-plate potentials, or EPPs) and spontane-

Regulation by Rab3A of an endogenous modulator of neurotransmitter release at mouse motor nerve endings

“…Adenosine acts by inhibiting the secretion of primed vesicles (Redman & Silinsky, 1994; Silinsky et al 2001). The increased potency of adenosine in the Rab3A −/‐ mouse raises the possibility that a substrate that normally regulates the potency of adenosine is absent in this mutant.…”

Phorbol esters and adenosine affect the readily releasable neurotransmitter pool by different mechanisms at amphibian motor nerve endings

“…1999). The characteristics of inhibition of ACh release by adenosine, stimulation independency and rapid onset, suggest that inhibition takes place at a late post‐priming stage in the release process (Silinsky et al . 2001).…”

“…It is known that the target for the inhibitory effect of adenosine at the amphibian neuromuscular junction is a strategic part of the secretory apparatus downstream of calcium entry (Silinsky, 1981(Silinsky, , 1984Robitaille et al 1999). The characteristics of inhibition of ACh release by adenosine, stimulation independency and rapid onset, suggest that inhibition takes place at a late post-priming stage in the release process (Silinsky et al 2001). (For a global review of the effects of adenosine at other synapses, see Miller, 1998.)…”

LY 294002 inhibits adenosine receptor activation by a mechanism independent of effects on PI-3 kinase or casein kinase II

“…In those experiments, wortmannin (100 nM) also blocked the phosphorylation of protein kinase B triggered by the A 1 receptor agonist N 6 -cyclopentyladenosine, leading to the suggestion that A 1 receptors mediate phosphorylation of protein kinase B through a PI-3 kinase dependent pathway in that system [ 18 ]. However, this mechanism does not seem likely at the frog neuromuscular junction as both the speed at which A 1 receptor activation inhibits transmitter release (< 100 ms [ 19 ]), and the failure of wortmannin to affect the sensitivity of evoked EPPs to adenosine, appears to preclude a role for PI-3 kinase as the mechanism by which adenosine inhibits transmitter release in this preparation.…”