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 ecto-nucleotidases. 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.