Abstract
A delayed rectifier voltage-gated K+ channel (Kv) represents the largest ionic conductance of platelets and megakaryocytes, but is undefined at the molecular level. Quantitative RT-PCR of all known Kv α and ancillary subunits showed that only Kv1.3 (KCNA3) is substantially expressed in human platelets. Furthermore, megakaryocytes from Kv1.3−/− mice or from wild-type mice exposed to the Kv1.3 blocker margatoxin completely lacked Kv currents and displayed substantially depolarised resting membrane potentials. In human platelets, margatoxin reduced the P2X1- and thromboxaneA2 receptor-evoked [Ca2+]i increases and delayed the onset of store-operated Ca2+ influx. Megakaryocyte development was normal in Kv1.3−/− mice, but the platelet count was increased, consistent with a role of Kv1.3 in apoptosis or decreased platelet activation. We conclude that Kv1.3 forms the Kv channel of the platelet and megakaryocyte, which sets the resting membrane potential, regulates agonist-evoked Ca2+ increases and influences circulating platelet numbers.
Highlights
Ion channels are a large and diverse family of transmembrane proteins that play important roles in all cell types. Their functions in the platelet are poorly understood, it is clear from patch clamp studies of platelets and megakaryocytes that the largest amplitude ionic currents are conducted through voltage-gated K+-selective (Kv) channels (Maruyama, 1987; Kawa, 1990; Kapural et al 1995; Romero & Sullivan, 1997)
We show for the first time that the voltage-gated K+ channel of the platelet and megakaryocyte is formed by Kv1.3 subunits, with no
The primary megakaryocyte is an authentic surrogate for electrophysiological studies of the small and fragile platelet (Tolhurst et al 2005), we used whole-cell patch clamp to investigate Kv currents of megakaryocytes from wild-type and Kv1.3-deficient mice
Summary
Ion channels are a large and diverse family of transmembrane proteins that play important roles in all cell types Their functions in the platelet are poorly understood (reviewed in Mahaut-Smith, 2004), it is clear from patch clamp studies of platelets and megakaryocytes that the largest amplitude ionic currents are conducted through voltage-gated K+-selective (Kv) channels (Maruyama, 1987; Kawa, 1990; Kapural et al 1995; Romero & Sullivan, 1997). We show for the first time that the voltage-gated K+ channel of the platelet and megakaryocyte is formed by Kv1.3 subunits, with no
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