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The Journal of Neuroscience, January 15, 2000, 20(2):606-616

P2Y Purinoceptors Inhibit Exocytosis in Adrenal Chromaffin Cells via Modulation of Voltage-Operated Calcium Channels

Andrew D. Powell, Anja G. Teschemacher, and Elizabeth P. Seward

Department of Pharmacology, University of Bristol, Bristol, BS8 1TD, United Kingdom

We have used combined membrane capacitance measurements (C_m) and voltage-clamp recordings to examine the mechanisms underlying modulation of stimulus-secretion coupling by a G_i/o-coupled purinoceptor (P2Y) in adrenal chromaffin cells. P2Y purinoceptors respond to extracellular ATP and are thought to provide an important inhibitory feedback regulation of catecholamine release from central and sympathetic neurons. Inhibition of neurosecretion by other G_i/o-protein-coupled receptors may occur by either inhibition of voltage-operated Ca²⁺ channels or modulation of the exocytotic machinery itself. In this study, we show that the P2Y purinoceptor agonist 2-methylthio ATP (2-MeSATP) significantly inhibits Ca²⁺ entry and changes in C_m evoked by single 200 msec depolarizations or a train of 20 msec depolarizations (2.5 Hz). We found that P2Y modulation of secretion declines during a train such that only ~50% of the modulatory effect remains at the end of a train. The inhibition of both Ca²⁺ entry and C_m are also attenuated by large depolarizing prepulses and treatment with pertussis toxin. Inhibition of N-type, and to lesser extent P/Q-type, Ca²⁺ channels contribute to the modulation of exocytosis by 2-MeSATP. The Ca²⁺-dependence of exocytosis triggered by either single pulses or trains of depolarizations was unaffected by 2-MeSATP. When Ca²⁺ channels were bypassed and exocytosis was evoked by flash photolysis of caged Ca²⁺, the inhibitory effect of 2-MeSATP was not observed. Collectively, these data suggest that inhibition of exocytosis by G_i/o-coupled P2Y purinoceptors results from inhibition of Ca²⁺ channels and the Ca²⁺ signal controlling exocytosis rather than a direct effect on the secretory machinery.

Key words: P2Y purinoceptor; G-protein-coupled receptor; voltage-operated calcium channels; exocytosis; modulation; presynaptic inhibition; adrenal chromaffin cells

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Copyright © 2000 Society for Neuroscience  0270-6474/00/202606-11$05.00/0

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