Introduction Ionotropic P2X receptors and metabotropic P2Y receptors are the principal cell surface proteins, conveying the action of extracellular ATP, the ubiquitous signaling substance. P2X receptors are ligand-gated cation channels, composed of three individual subunits, whereas P2Y receptors belong to the superfamily of G protein-coupled receptors (GPCRs), with seven transmembrane domains. Various subtypes of P2X and P2Y receptor families are expressed throughout the brain and involved in a wide array of functions from fast synaptic transmission to long-term plasticity and trophic changes important for development, neuron-glia interactions, and neuroimmunomodulation. In addition, ATP modulates synaptic transmission pre- and postsynaptically, both in a positive and negative direction via activation of P2X and P2Y receptors, respectively. 1 4 2+ 2+ 2 4 3 5 6 7 The focus of this mini-review is the facilitatory and inhibitory modulation of neurotransmitter release by different subtypes of P2X and P2Y receptors, irrespective of their localization, i.e., whether they are pre-, post-, or extrasynaptic. Therefore, in addition to a brief summary of the determining factors of ATP availability in synapses, the structure, pharmacology, signal transduction, and distribution of P2X and P2Y receptors in the nervous system, available information on the release-modulating P2 receptors, and the receptor subtypes involved in these interactions will be detailed and updated. Determining factors of ATP availability in synapses The participation of ATP and related nucleotides in the regulation of neurotransmitter release presumes their accumulation in the extracellular space upon ongoing neuronal activity. Extracellular purine availability in the nervous system is basically determined by the balance of release and removal by enzymatic degradation and uptake. Sources and stimuli that trigger ATP release 8 9 10 11 12 13 14 15 17 18 19 20 25 26 27 28 29 Mechanisms of ATP release 2+ o 8 15 2+ o 8 9 24 30 31 32 15 19 33 34 35 36 37 38 39 40 31 41 42 Metabolism of ATP in the extracellular space 14 43 44 m 14 1 2A 2B 3 1 45 46 47 Structure, pharmacology, and signal transduction of P2X receptors 48 49 1 7 50 51 6 1 6 N 6 52 7 + + 2+ 2+ 7 50 53 2/3 2/6 1/2 1/4 1/5 4/6 54 59 The distribution of P2X receptors in neuronal structures 60 2 4 6 60 63 2 61 64 65 62 1 60 63 66 3 67 69 4 70 62 5 71 7 72 7 73 75 7 7 76 77 7 7 78 7 7 7 Structure, pharmacology, and signal transduction of P2Y receptors 79 82 1 2 4 6 11 12 13 14 1, 12 13 6 2, 4 11 14 N 83 84 85 45 47 1 86 1 2 4 6 11 q/11 2+ 11 84 12 13 14 i/o 84 i 2+ 85 2+ q/11 85 85 i/o + 85 The distribution of P2Y receptors in neuronal structures 1 2 4 6 12 13 14 81 87 89 1 2 6 90 96 13 97 14 98 12 99 12 100 85 85 101 Modulation of neurotransmitter release by facilitatory P2 receptors ACh PNS P2X receptors 2+ 102 103 2+ 2+ 1 6 6 Xenopus 2+ 104 105 106 Xenopus 107 108 7 74 109 Table 1 Facilitatory modulation of neurotransmitter release in the PNS and CNS Preparation Measured effect Proposed receptor Reference Acetylcholine     Guinea pig ileum NT quantification P2 6  Chicken ciliary ganglion Presynaptic current P2X 105 Xenopus sEPP/mEPP P2 104 107  Mouse NMJ EPP/mEPP P2 106  Mouse NMJ Vesicular destaining, EPSC 7 74 109  Rat NMJ NT quantification P2X 108 Noradrenaline     Rabbit ear artery EJP P2 110  PC12 cells NT quantification P2 111  Guinea pig ileum NT quantification P2 6  Rat vas deferens NT quantification 1 3 2/3 113  Guinea pig atrium NT quantification 3 2/3 114 115 118  Human and porcine heart NT quantification P2X 119  Sympathetic neurons NT quantification 2 116  LC neurons AP discharge P2X 120  Rat hippocampus NT quantification 1 3 68 Serotonin     Rat hippocampus NT quantification P2 121 Dopamine     Rat striatum NT quantification P2Y 122 123  Rat nucleus accumbens NT quantification P2 124 128 Glutamate     Rat brainstem mEPSC/NT quantification 1 131 157  Rat NTS EPSC 3 2/3 129 130 132  Rat hippocampus NT quantification 1 3 2/3 69  Rat hippocampus NT quantification 7 75  Mouse hippocampus NT quantification 7 137  Rat hippocampus EPSC 2 133  Rat hippocampus EPSC 7 134  Rat hippocampal neurons EPSC P2 135  Rat cortical synaptosomes NT quantification 7 136  Cultured astrocytes NT quantification 7 142  Retinal Müller glial cells NT uptake 7 143  Rat spinal cord EPSC/mEPSC 3 1/5 4/6 144 148  Rat nucleus accumbens NT quantification P2 149  Rat medial habenula EPSC 4 150  Cultured astrocytes NT quantification 1 151  Cultured Schwann cells NT quantification P2 152 GABA     Midbrain synaptosomes NT quantification 3 153  Cultured dorsal horn neurons IPSC P2X 154  Cultured hippocampal cells IPSC P2 156  Cultured cortical cells NT quantification 7 155  Rat brainstem IPSC 1 157  Rat, mouse, and guinea pig hippocampus NT quantification/IPSC 7 75 137 158  Cultured astrocytes NT quantification 7 159  Rat hippocampus IPSC 1 163 206 Glycine     Rat dorsal horn IPSC P2X 161  Rat trigeminal nucleus sIPSC P2X 162 AP EJP EPP EPSC IPSC mEPP mEPSC NMJ NT sEPP sIPSC Monoamines (NA, serotonin, DA) PNS P2X receptors 110 3 111 6 1 112 115 2+ 2 116 3 2 3 115 1 3 2 3 113 117 115 116 118 119 CNS P2X receptors 120 1 3 68 P2Y receptors 121 122 123 124 126 127 128 Excitatory amino acids (glutamate, aspartate) CNS P2X receptors 129 132 69 75 133 135 136 1 69 2 133 3 2/3 69 130 7 75 132 134 136 137 2 133 7 137 2 7 7 136 7 2+ 138 139 140 140 7 7 141 7 76 77 7 142 143 144 148 144 3 1/5 4/6 149 P2Y receptors 4 150 1 151 152 Inhibitory amino acids (GABA, glycine) CNS P2X receptors 5 3 153 154 155 156 3 1 157 7 75 7 137 75 158 7 3 - - 159 160 161 162 P2Y receptors 1 163 Modulation of neurotransmitter release by inhibitory P2 receptors 2 Table 2 Inhibitory modulation of neurotransmitter release in the PNS and CNS Preparation Measured effect Proposed receptor Reference Acetylcholine     Frog ganglion EPSC P2 165  Guinea pig ileum NT quantification P2 164 166 167  Ileal synaptosomes NT quantification P1 168  Guinea pig submucosal neurons EJP P3 169  Frog NMJ EPP P2 170  Rat submandibular ganglion EPSC P2 171  Rabbit retina NT quantification P2 172  Mouse NMJ sEPP P2Y 173 Noradrenaline     Mouse vas deferens NT quantification P2Y-like 5 174 181 182  Rat vas deferens NT quantification P3 178  Rat vas deferens NT quantification P2Y 181  Rat vas deferens NT quantification 12 13 113  Guinea pig vas deferens NT quantification P2Y-like 179  Guinea pig saphenous artery EJP P2 175  Rat caudal artery NT quantification P3, P2Y 176 177 180  Rat atrium NT quantification P2Y-like 183  Rat iris NT quantification P2Y-like 184  Rat kidney NT quantification P2 185  Rat pancreas NT quantification P2 186  Chick sympathetic neurons NT quantification 12 187 188 189  Bovine chromaffin cells NT quantification P2Y12 190 194  Rat cortex NT quantification P2Y 195  Rat hippocampus NT quantification P2Y 196 Serotonin     Rat cortex NT quantification P2 197 Dopamine     Rat striatum NT quantification P2 198 Glutamate     Rat cortex EPSC P2 199  Rat hippocampus EPSC P2Y 200 201  Rat spinal cord Polysynaptic EPSP P2Y 204  Hippocampal slice culture EPSC P2Y 205 EJP EPP EPSC EPSP NMJ NT SEPP ACh PNS 164 165 167 168 169 170 171 172 173 i/o 2+ 173 CNS 47 1 47 Monoamines (NA, serotonin, DA) PNS 5 174 179 5 176 178 176 177 180 175 5 178 179 181 182 183 184 185 186 187 188 113 12 13 189 190 12 191 192 2+ 2+ 189 193 194 CNS 195 196 197 198 Excitatory amino acids (glutamate, aspartate) CNS 199 200 45 46 1 -/- 201 1 2 4 69 202 203 204 1/12/13 204 2+ 205 1 205 1 206 Potential therapeutic utilization of P2 receptors involved in the regulation of neurotransmitter release 118 119 207 Conclusion 1 2 3 2/3 1/5 4/6 7 1 4 12 13