title: Chlorpromazine-induced changes in membrane micro-architecture inhibit thrombopoiesis in rat megakaryocytes.
abstract: Chlorpromazine often causes severe and persistent thrombocytopenia. Several clinical studies have suggested the presence of an as-yet-unknown mechanism in this drug-induced thrombocytopenia, by which the platelet production from megakaryocytes may directly be affected. As we previously demonstrated in rat peritoneal mast cells or adipocytes, chlorpromazine is amphiphilic and preferentially partitioned into the lipid bilayers of the plasma membrane. Therefore, it can induce some structural changes in the megakaryocyte membrane surface and thus affect the process of thrombopoiesis. In the present study, employing the standard patch-clamp whole-cell recording technique, we examined the effects of chlorpromazine on the membrane capacitance and Kv1.3-channel currents in rat megakaryocytes. By electron microscopic imaging of the cellular surface, we also examined the effects of chlorpromazine on the membrane micro-architecture of megakaryocytes. Chlorpromazine markedly decreased the membrane capacitance of megakaryocytes, indicating the decreased number of invaginated plasma membranes, which was not detected by the fluorescent imaging techniques. As shown by electron microscopy, chlorpromazine actually changed the membrane micro-architecture of megakaryocytes, and was likely to halt the process of pro-platelet formation in the cells. This drug persistently decreased the membrane capacitance and almost totally and irreversibly inhibited the Kv1.3-channel currents in megakaryocytes. This study demonstrated for the first time that chlorpromazine is likely to inhibit the process of thrombopoiesis persistently in megakaryocytes, as detected by the long-lasting decrease in the membrane capacitance and the irreversible suppression of the Kv1.3-channel currents. Chlorpromazine-induced changes in the membrane micro-architecture are thought to be responsible for its persistent effects.
authors: Department of Physiology I, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan. Electronic address: kazaitsu@med.tohoku.ac.jp.
authors: Itsuro
authors: I
authors: Kazama
authors: Department of Anesthesiology, Tohoku University Hospital, Japan.
authors: Yutaka
authors: Y
authors: Ejima
authors: Department of Anesthesiology, Tohoku University Hospital, Japan.
authors: Yasuhiro
authors: Y
authors: Endo
authors: Department of Anesthesiology, Tohoku University Hospital, Japan.
authors: Hiroaki
authors: H
authors: Toyama
authors: Division of Molecular Medicine, Center for Translational and Advanced Animal Research, Tohoku University Graduate School of Medicine, Japan.
authors: Mitsunobu
authors: M
authors: Matsubara
authors: Department of Physiology I, Tohoku University Graduate School of Medicine, Seiryo-cho, Aoba-ku, Sendai, Miyagi, Japan; Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Japan.
authors: Asuka
authors: A
authors: Baba
authors: Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Japan.
authors: Masahiro
authors: M
authors: Tachi
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D025802:Electric Capacitance; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D051664:Kv1.3 Potassium Channel / Q000378:metabolism / Q000502:physiology; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008854:Microscopy, Electron; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D034061:Thrombopoiesis / Q000187:drug effects*
chemical_list: D018492:Dopamine Antagonists; D051664:Kv1.3 Potassium Channel; D002746:Chlorpromazine
keywords: Chlorpromazine; Megakaryocytes; Membrane capacitance; Membrane micro-architecture; Thrombopoiesis