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1 From the Department of Neurophysiology, Paul Flechsig Institute of Brain Research, University of Leipzig, Leipzig, Germany.
PURPOSE. To determine whether activation of P2Y receptors may increase the DNA synthesis rate of cultured Müller cells and to investigate whether adenosine 5'-triphosphate (ATP)–induced Müller cell proliferation is mediated by an intracellular calcium increase.
METHODS. Primary cultures of Müller cells of the guinea pig were treated with test substances for 16 hours. The DNA synthesis rate was assessed by a bromodeoxyuridine immunoassay, and ATP-induced elevations of the intracellular calcium concentration were recorded by fura-2 imaging.
RESULTS. ATP or uridine triphosphate (UTP) increased the DNA synthesis
rate whereas 
,ß-methylene-ATP, 2-methyl-thio-ATP, and adenosine
were ineffective, indicating that the action of ATP was through P2Y
receptors. The effect of ATP was dose dependent, with an
EC50 of 5.9 µM. The mitogenic effect of ATP required an
elevation of the intracellular calcium and a calcium influx into
Müller cells. Blockers of calcium-permeable channels (nickel
ions) or of calcium-dependent potassium (BK) channels (iberiotoxin,
charybdotoxin) inhibited the ATP-stimulated DNA synthesis. In
calcium-imaging experiments, ATP-evoked intracellular calcium
transients were significantly shortened in the presence of
extracellular nickel ions or of iberiotoxin. A correlation was found
between the duration of the ATP-evoked calcium transients and the basal
proliferation rate of the cultures.
CONCLUSIONS. The results indicate that the ATP-induced elevation of Müller glial DNA synthesis is dependent on an influx of calcium ions from the extracellular space and that the inhibiting effect of BK channel blockers on ATP-evoked DNA synthesis is caused by an inhibition of this influx. The amount of the calcium influx seems to be directly correlated to the strength of the ATP-evoked proliferation.
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