A study of P2X1 receptor function in murine megakaryocytes and human platelets reveals synergy with P2Y receptors

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Abstract
We have examined the role of ATP‐dependent P2X1 receptors in megakaryocytes (MKs) and platelets using receptor‐deficient mice and selective agonists. α,β‐meATP‐ and ATP‐ evoked ionotropic inward currents were absent in whole‐cell recordings from MKs of P2X1−/− mice, demonstrating that the P2X receptor phenotype in MKs, and by inference, platelets, is due to expression of homomeric P2X1 receptors. P2X1 receptor deficiency had no effect on MK (CD 41) numbers or size distribution, showing that it is not essential for normal MK development. P2Y receptor‐stimulated [Ca2+]i responses were unaffected in MKs from P2X1−/− mice, however the inward cation current associated with Ca2+ release was reduced by ∼50%, suggesting an interaction between the membrane conductances activated by P2X1 and P2Y receptors. Interaction between P2X1 and P2Y receptors in human platelets was also examined using [Ca2+]i recordings from cell suspensions. α,β‐meATP (10 μM) evoked a rapid transient P2X1 receptor‐mediated increase in [Ca2+]i, whereas ADP‐(10 μM) evoked P2Y receptor responses were slower, peaked at a higher level and remained elevated for longer periods. Co‐application of α,β‐meATP and ADP resulted in marked acceleration and amplification of the peak [Ca2+]i response. We conclude that ionotropic P2X1 receptors may play a priming role in the subsequent activation of metabotropic P2Y receptors during platelet stimulation. British Journal of Pharmacology (2002) 135, 363–372; doi:10.1038/sj.bjp.0704486