Introduction 1 2 3 2 4 5 6 8 9 10 1 11 12 13 16 http://mgddk1.niddk.nih.gov/ http://www.ensembl.org/index.html http://www.geocities.com/bioinformaticsweb/speciesspecificdatabases.htm 17 20 Ensembles of ectonucleotidases, associated receptors and signaling molecules 21 25 26 10 27 28 30 Molecular identities unraveled 18 22 31 36 ENTPD 1 1 1 Table 1 Nomenclature of mammalian members of the E-NTPDase family and chromosomal localization Protein name Additional names Gene name human, mouse Chromosome location human, mouse Accession number human, mouse NTPDasel 43 44 ENTPD1, Entpdl 10q24, 19C3 U87967, NMJ309848 NTPDase2 49 109 252 ENTPD2, Entpdl 9q34, 2A3 AF144748, AY376711 NTPDase3 50 177 ENTPD3, Entpd3 3p21.3, 9F4 AF034840, AY376710 NTPDase4 253 254 ENTPD4, Entpd4 8p21, 14D1 AF016032, NMJ326174 NTPDase5 137 255 256 ENTPD5, Entpd5 a AF039918, AJ238636 NTPDase6 257 259 ENTPD6, Entpd6 20p11.2, 2G3 AY327581, NM_172117 NTPDase7 260 ENTPD7, Entpd7 a AF269255, AF288221 NTPDase8 52 174 ENTPD8, Entpd8 9q34, 2A3 AY430414, AY364442 http://www.ncbi.nlm.nih.gov http://www.informatics.jax.org/ a Entpd5 Entpd7 Fig. 1 r h m length of the lines graph top bottom barrels 59  17 37 40 41 42 43 44 44 45 46 47 48 49 51 CD39L(ike)1 CD39L4 52 34 53 54 50 55 34 56 Catalytic properties 2+ 2+ 34 57 1 2 34 57 2+ 2+ 52 58 59 60 61 Fig. 2 figure via Bottom figure 57  2 57 2 1 12 62 Principal structural features 42 63 64 30 34 64 68 42 47 69 70 30 59 71 59 3 30 72 Fig. 3 59 80  29 64 73 78 73 75 76 77 78 29 64 79 29 61 80 3 Functional modifications 81 82 64 83 13 84 86 87 35 88 86 20 Transcriptional regulation of expression 22 20 89 in vitro in vivo 19 90 91 92 in-vitro 93 94 95 96 97 98 99 100 Inhibitors 22 101 102 N N 103 105 106 101 107 Torpedo 108 109 111 Principal functional contexts in situ 20 112 113 114 116 117 112 118 121 2 122 122a splA RyR 123 124 47 1 2 125 126 128 + 129 Xenopus 130 Vasculature 131 19 82 20 44 82 132 133 19 2 4 2 113 134 136 Fig. 4 Entpd1 261 n Entpd1  112 32 50 137 81 132 138 1 12 62 in vivo 19 82 139 in vitro 81 134 Mechanisms of endothelial cell activation by nucleotides 140 142 143 cas 144 20 112 Therapeutic considerations Entpd1,cd39 19 89 145 20 112 134 20 146 147 133 148 148 149 Entpd1 145 150 151 153 20 134 4 20 133 20 154 155 Immune system 2 156 157 89 + + 156 157 cd39 19 89 19 89 158 159 reg 160 reg Digestive and renal systems 2 161 162 163 164 Liver 161 165 166 167 169 161 168 in vitro 170 in vitro in vivo 171 172 173 174 175 176 50 177 161 175 117 99 178 179 181 52 174 182 183 184 17 185 167 186 185 167 The exocrine pancreas 3 187 188 189 190 191 192 193 194 188 195 194 Salivary glands 194 196 Kidney 197 198 174 199 200 199 174 201 The nervous system 2 22 31 36 202 2+ 203 204 205 36 206 207 208 Central nervous system 209 210 202 211 in situ 47 57 59 116 177 212 213 214 22 31 36 215 Neurons 216 217 2 218 Astrocytes, oligodendrocytes, and microglia 219 220 221 222 in situ 223 31 224 225 Stem cells in the adult mammalian brain 226 221 5 222 1 2 227 Fig. 5 SVZ triple labeling A Arrow heads B B stars D B E Bar  59 228 116 Peripheral nervous system 229 230 231 231 Sensory systems 232 233 234 235 236 2 3 237 238 239 2 3 240 241 Pathological implications Cerebral ischemia 20 242 243 243 242 224 7 244 245 Alterations following plastic changes in the nervous system 246 247 248 249 250 251 Conclusions This review summarizes components of extracellular nucleotide-mediated signaling pathways that are impacted upon largely by the E-NTPDase family of ectonucleotidases. Modulated, distinct NTPDase expression appears to regulate nucleotide-mediated signaling in essentially every tissue, including the vasculature and of immune and nervous systems. For example, extracellular nucleotide-mediated vascular endothelial and accessory cell stimulation might have important consequences for platelet activation, thrombogenesis, angiogenesis, vascular remodeling and the metabolic milieu of the vasculature, in response to inflammatory stress and/or immune reactions. Nucleotides are also of significant relevance for the communication of nerve cells and glial cells or in the reciprocal signaling between these cells. These purinergic mechanisms might also dictate pathological processes of the nervous system or following vascular injury, thromboregulatory disturbances, and defective angiogenesis with associated perturbations in tissue remodeling and regeneration. There is a wide field for future investigations of the role of nucleotides and ectonucleotidases in other tissues. Increasing interest in this field may open up new avenues for investigation and the development of new treatment modalities for a large variety of diseases, including neurological pathological states, vascular thrombotic disorders including stoke, atherosclerosis and the vascular inflammation seen in transplant-graft failure.