ATP as a cotransmitter in perivascular sympathetic nerves.

1. P2X-receptors are ligand-gated ion channels which activate within milliseconds of agonist binding, causing rapid cellular depolarization and excitation. This makes them ideally suited to mediate the rapid neurotransmitter functions of adenosine 5'-triphosphate (ATP). 2. The initial postjunctional response of the vas deferens and most blood vessels to sympathetic nerve stimulation is a rapid, transient excitatory junction potential (EJP). With sufficient stimulation EJPs summate and the membrane depolarizes sufficiently to open voltage-dependent calcium channels, initiating a calcium action potential and contraction. 3. EJPs are inhibited by desensitization of the P2X-receptor by the stable agonist alpha, beta-methyleneATP (alpha, beta-meATP) and by the P2X-receptor antagonists ANAPP3, suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid, indicating that they are consequent upon activation of the P2X-receptor. 4. The P2X-receptor was originally defined by contractile studies in smooth muscle preparations, where a rank order of agonist potency of alpha, beta-meATP > > 2-methylthioATP (2-meSATP) > or = ATP was found. However, recent results show that the potency of ATP and 2-meSATP, but not alpha, beta-meATP, is decreased by 100-to 1000-fold by breakdown and when this is prevented, ATP and 2-meSATP are more potent than alpha, beta-meATP as agonists at the P2X-receptor. 5. This conclusion was supported by the cloning and functional expression of the P2X1-receptor from the rat bladder. A total of seven P2X-subunits have since been cloned and the P2X1-subunit is thought to be the predominant subunit expressed in vascular smooth muscle cells.