Historical overview 1 2 1 2A 2B 3 3 4 5 6 Roles of ATP in neurotransmission under normoxic conditions 7 8 1 7 9 1 10 11 1 3 12 14 15 11 16 17 18 Ki 19 Ki 20 1 Fig. 1a, b a  point b  Columns P P 15  21 25 26 2 15 3 27 Fig. 2 n  Upper panels  Fig. 3  Bars P  t 15  Roles of ATP in ischemic conditions 28 29 2+ 7 1 15 15 30 33 34 34 35 36 37 7 7 7 36 38 1 12 12 39 40 41 43 44 2+ 45 2+ 2+ 4 46 Fig. 4a, b a n t P b  column bar n t P P 46  47 29 Role of adenosine in cerebral transmission under normoxic conditions 1 48 49 1 1 2+ 50 51 52 1 53 54 55 1 56 1 57 58 1 59 59 60 1 1 61 1 2A 62 64 2A 2+ 65 66 2A 1 9 67 2A 1 68 69 2A 2A 70 72 2A 2A 59 2A 2 2A 2 2A 73 74 2A 3 3 75 3 3 1 8 3 76 3 2+ 77 3 78 3 79 3 80 1 3 3 3 8 81 3 82 85 Role of adenosine in ischemic conditions 82 86 87 5 88 Fig. 5  ADP  AMP  ATP  e5′-NT 5′-NT  NTDPase  P1  P2  SAH  T 142  89 90 91 92 93 84 88 1 2+ 55 94 95 + − 96 97 98 1 99 100 1 1 101 102 1 103 1 1 1 104 105 1 106 2A 107 2A 2A 2A 108 83 109 110 111 2A 2A 112 2A 83 110 113 2A  59 70 71 114 115 2A 116 117 118 2A 119 2A 120 2A 2A 2A 111 121 122 123 124 83 2A 125 2A 2A 126 2A 2A 127 2A 2A 128 129 130 2A 2A 131 2A 2A 89 2A 132 133 2A 134 3 3 81 3 3 135 3 136 3 136 3 3 137 138 139 3 3 1 3 140 141 3 135 3 1 3 3 Concluding remarks Purinergic signalling, e.g. adenosine and ATP, by activating specific membrane receptors (P1 and P2 respectively), is strictly correlated in orchestrating brain cell functions either under physiological normoxic or ischemic circumstances. However, the respective contribution of each single element is hard to discern from the total outcome, due to the rapid and ubiquitous enzymatic interconversion of these molecules. 1 1 1 2A 3 Purinergic signalling has an ancient phylogenetic origin. Expression of P2 receptors on cell membrane and responses to extracellular ATP are found in primitive prokaryotic species up to evolved animals and plants, suggesting an important and highly conserved role of extracellular purine nucleotides during evolution. Similarly, ontogenetic development in several species seems to involve purinergic signalling, especially during its first stages. Our observation that hMSCs, an undifferentiated line of cells able to originate a number of different cell lineages (adipocytes, chondrocytes, osteoblasts, neurones), spontaneously release ATP into the extracellular space and express functional purinergic P2 receptors, which modulate different kinds of membrane currents, and that ATP, during the early stages of culture, inhibits proliferation indicates an autocrine/paracrine mechanism of action for extracellular ATP in modulating cell functions of undifferentiated stem cells at early developmental stages. Such effects may be important in brain neurogenesis during development and in responses to neurodegenerative stimuli.