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HERBERT ZIMMERMANN Y COLS. AN. R. ACAD. NAC. FARM.

biological action of ATP on several mammalian tissues (11). Other
support for a potential extracellular function of ATP came from the
discovery of its storage inside secretory granules of a variety of cells
such as dense granules of blood platelets (12, 13), chromaffin
granules (14, 15) and later adrenergic (16) and cholinergic (17)
synaptic vesicles (18). ATP was found to be costored with the
neurotransmitters noradrenaline and acetylcholine. On nerve
stimulation, ATP is depleted from cholinergic synaptic vesicles
in parallel with acetylcholine and replenished together with
acetylcholine during a subsequent period of rest. Adenosine taken up
into cholinergic nerve terminals via a high affinity transporter is
immediately phosphorylated and ends up again in synaptic vesicles
in the form of ATP that is coreleased with acetylcholine (adenosine
cycle) (19, 20).

The notion of cell surface-located ATPases reaches back into the
1940ies. To the best of knowledge, first cell surface-located hydrolysis
of ATP was observed in carefully washed bull spermatozoa by T. Mann
in Cambridge in 1945 (21). More detailed reports followed on the
hydrolysis of ATP and ADP by intact yeast cells (22) and subsequently
in human erythorcytes (23), ascites tumor cells (24) and nucleated
avian erythrocytes (25, 26). First evidence for an association of ATPase
activity with peripheral nerves was obtained by Abood and Gerard in
1954 (27). The pioneering methodological work of Wachstein and
Meisel (1957) (28) paved the way for the enzyme cytochemical
demonstration of ATP hydrolysis at the electron microscopic level that
revealed the ubiquity of cell surface located ATPase activity. Essner et
al. (1958) (29) were among the first to use the electron microscope to
localize adenosine triphosphatase and 5’-nucleotidase activities at
the plasma membrane. The term ecto-ATPase was coined in 1957
by W.A. Engelhardt from the Academy of Sciences in Moscow on
the basis of his findings of surface-located ATPase activity on avian
blood cells (25). He also introduced the terms ectoenzyme and
ectoapyrase (26). Yet, the functional role of extracellular ATP
hydrolysis remained a matter of speculation. As for the concept of
nucleotide receptors, the concept of extracellular nucleotide
hydrolysis was met by the scientific community with great skepticism.

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