Perspectives in Pharmacology ATP as a Cotransmitter in Sympathetic Nerves and Its Inactivation by Releasable Enzymes

ATP and norepinephrine (NE) are cotransmitters released from many postganglionic sympathetic nerves. In this article, we review the evidence for ATP and NE cotransmission in the rodent vas deferens with special attention to the mechanisms involved in removing the cotransmitters from the neuroeffector junction. Although the clearance of NE is well understood (e.g., the primary mechanism being reuptake into the nerves), the clearance of ATP is just beginning to be explained. The general belief has been that ATP is metabolized by cell-fixed ectonucleotidases. It now seems, however, that when ATP is released from nerves as a transmitter there is a concomitant release of nucleotidases that rapidly degrade ATP sequentially to ADP, AMP, and adenosine, thereby terminating the action of ATP. In the guinea pig vas deferens, there appear to be at least two enzymes, one that converts ATP to ADP and ADP to AMP (an ATPDase) and a second enzyme that converts AMP to adenosine (an AMPase). An important feature of this process is that the transmitter-metabolizing nucleotidases are released into the synaptic space as opposed to being fixed to cell membranes. A preliminary characterization of these enzymes suggests that the releasable ATPDase exhibits some similarities to known ectonucleoside triphosphate/diphosphohydrolases, whereas the releasable AMPase exhibits some similarities to ecto-5 -nucleotidases. The evidence is now substantial that ATP plays a role in sympathetic neuroeffector mechanisms as a cotransmitter with norepinephrine (NE) (Stjarne, 1989; Westfall et al., 1991; Silinsky et al., 1998; Burnstock, 1999). Much of the early evidence implicating ATP as a cotransmitter came from studies of the rodent vas deferens, and work in the authors’ laboratory, as well as by others, has contributed to this knowledge (see Sneddon and Westfall, 1984). This article will briefly review the current understanding of ATP and NE cotransmission using the vas deferens as a model and, further, will discuss more recent information about an unusual mechanism that links inactivation of ATP to nerve stimulation-induced release of degrading enzymes. Cotransmission in Vas Deferens The vas deferens is supplied with a dense sympathetic innervation, and stimulation of the nerves results in a biphasic mechanical response that consists of an initial rapid twitch, followed by a maintained contraction (see Westfall and Westfall, 2001). The evidence is now clear that the first phase of the response is mediated mainly by ATP acting on postjunctional P2X receptors, whereas the second phase is mediated mainly by NE acting on 1-adrenoceptors (Fig. 1). Activation of P2X receptors by ATP results in the production of excitatory junction potentials that summate to produce action potentials, which then propagate from one smooth muscle cell to another (Sneddon et al., 1982; Sneddon and Westfall, 1984). The calcium influx that results from depolarization leads to the generation of a major component of the first phase of the contraction. The activation of the 1-adrenoceptors by NE results mainly in the second maintained phase of the contraction, by a mechanism that involves the release of intracellular calcium by a phosphoinositide pathResearch referenced from the authors’ laboratory was supported by National Institutes of Health Grants HL 38126 and NS 08300 and a grant from the Foundation for Research. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. DOI: 10.1124/jpet.102.035113. ABBREVIATIONS: NE, norepinephrine; NPY, neuropeptide Y; ENPPases, ectonucleotide pyrophosphatase/phosphodiesterases; ENTPDases, ectonucleoside triphosphate/diphosphohydrolases; EFS, electrical field stimulation; ADO, adenosine; ARL 67156, 6-N-N-diethyl, -dibromomethylene-D-ATP. 0022-3565/02/3032-439–444$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 303, No. 2 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 35113/1021259 JPET 303:439–444, 2002 Printed in U.S.A. 439 at A PE T Jornals on Jne 4, 2017 jpet.asjournals.org D ow nladed from