Kv1.3 is the exclusive voltage‐gated K+ channel of platelets and megakaryocytes: roles in membrane potential, Ca2+ signalling and platelet count

• Published in: The Journal of physiology Vol. 588; no. 9; pp. 1399 - 1406
• Main Authors: McCloskey, Conor, Jones, Sarah, Amisten, Stefan, Snowden, Roger T., Kaczmarek, Leonard K., Erlinge, David, Goodall, Alison H., Forsythe, Ian D., Mahaut‐Smith, Martyn P.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-05-2010; Wiley Subscription Services, Inc; Blackwell Science Inc
• Subjects: Animals; Blood platelets; Blood Platelets - drug effects; Blood Platelets - physiology; Blood Platelets - ultrastructure; Calcium Signaling - drug effects; Calcium Signaling - physiology; Cell Size; DNA, Complementary - biosynthesis; DNA, Complementary - genetics; Humans; In Vitro Techniques; Kv1.3 Potassium Channel - blood; Megakaryocytes - drug effects; Megakaryocytes - physiology; Megakaryocytes - ultrastructure; Membrane Potentials - drug effects; Membrane Potentials - physiology; Mice; Mice, Inbred C57BL; Molecular and Cellular; Patch-Clamp Techniques; Platelet Count; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Scorpion Venoms - pharmacology; Second Messenger Systems - physiology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2010.188136

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.
Platelets are blood cells that trigger blood clotting and so prevent blood loss after injury. Inappropriate platelet activation generates clots within the blood stream which then block blood vessels (thrombosis), a major cause of stroke and heart attacks. Ion channels are trans‐membrane proteins, which control ion flow (ions are charged atoms in solution for example K+, Na+ or Cl−) and hence the voltage across cell membranes. This study shows that a specific channel, named Kv1.3 (voltage‐gated potassium channel family 1 subtype 3), is responsible for large ion currents in the platelet and its ‘parent’ cell, the megakaryocyte. This channel regulates influx of calcium ions which, in turn, trigger platelet activation. Kv1.3 also influences the number of circulating platelets, possibly by affecting their lifespan.