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Received October 14, 2003
Revised October 29, 2003
Accepted after revision November 25, 2003
1 University of Cambridge
2 Victor Chang Cardiac Research Institute
* To whom correspondence should be addressed. E-mail: mpm11{at}cam.ac.uk.
G-protein-coupled receptor signalling has been suggested to be voltage-dependent in a number of cell types, however the limits of sensitivity of this potentially important phenomenon are unknown. Using the non- excitable rat megakaryocyte as a model system, we now show that P2Y receptor-evoked Ca2+ mobilization is controlled by membrane voltage in a graded and bipolar manner without evidence for a discrete threshold potential. Throughout the range of potentials studied, the peak increase in intracellular Ca2+ concentration ([Ca2+] i) in response to depolarization was always larger than the maximal reduction in [Ca2+] i following an equivalent amplitude hyperpolarization. Significant [Ca2+] i increases were observed in response to small amplitude (<5 mV, 5s duration) or short duration (25 ms, 135 mV) depolarizations. Individual cardiac action potential waveforms were also able to repeatedly potentiate P2Y receptor-evoked Ca2+ release and the response to trains of normally paced stimuli fused to generate prolonged [Ca2+] i increases. Furthermore, elevation of the temperature to physiological levels (36oC) resulted in a more sustained depolarization-evoked Ca2+ increase compared with more transient or oscillatory responses at 20-24oC. The ability of signalling via a G-protein-coupled receptor to be potentiated by action potential waveforms and small amplitude depolarizations has broad implications in excitable and non-excitable tissues.
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