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The Journal of Neuroscience, August 20, 2003, 23(20):7479-7488

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Activity-Dependent Autocrine-Paracrine Activation of Neuronal P2Y Receptors

Eugenia Moskvina, Ursula Unterberger, and Stefan Boehm

Institute of Pharmacology, University of Vienna, A-1090 Vienna, Austria

Activation of P2Y receptors by released nucleotides subserves important autocrine-paracrine functions in various non-neural tissues. To investigate how P2Y receptors are activated in a neuronal environment, we used PC12 cells in which nucleotides were found to elicit increases in inositol phosphates via P2Y₂ and decreases in cAMP via P2Y₁₂ receptors. Depolarization of PC12 cells raised inositol phosphates, and blockade of voltage-gated Ca²⁺ channels by Cd²⁺ or degradation of extracellular nucleotides by apyrase prevented this effect. In nondepolarized cells, apyrase did not affect inositol phosphates. Depolarization of PC12 cells also reduced the A_2A receptor-mediated synthesis of cAMP. This effect was again prevented by Cd²⁺ or apyrase, but apyrase enhanced the synthesis of cAMP even in nondepolarized cells. Overexpression of rat P2Y₂ receptors increased the nucleotide-dependent inositol phosphate accumulation and enhanced the effect of K⁺ depolarization. Nevertheless, apyrase still failed to alter spontaneous inositol phosphate accumulation. Expression of rat P2Y₁ receptors, in contrast, led to huge increases in spontaneous inositol phosphate accumulation, which was reduced by a receptor antagonist or by apyrase. This increased synthesis of inositol phosphates could not be further enhanced by depolarization or receptor agonists, but when endogenous nucleotides were removed by superfusion, recombinant P2Y₁ receptors could be activated to mediate an inhibition of M-type K⁺ channels. These results indicate that nucleoside diphosphate-sensitive (P2Y₁₂ and P2Y₁) receptors are activated by spontaneous nucleotide release, whereas triphosphate-sensitive (P2Y₂) receptors require an excess of depolarization-evoked release to become activated.

Key words: P2Y receptors; inositol phosphates; cAMP; M-type K⁺ current; PC12 cells; nucleotide release

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Received Feb. 27, 2003; revised Jun. 13, 2003; accepted Jun. 16, 2003.

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