title: Drug-induced endovesiculation of erythrocytes is modulated by the dynamics in the cytoskeleton/membrane interaction.
abstract: Recent studies on erythrocyte membrane fluctuations revealed that the erythrocyte cytoskeleton actively modulates its membrane association thereby regulating crucial membrane properties. Cationic amphiphilic drugs like chlorpromazine are known to induce a cup-like cell shape and vesicle formation into the cell interior, effectors of this process, however, are largely unknown. Using flow cytometry, this study explored conditions that influence endovesiculation induced by chlorpromazine. We found that inhibitors of membrane fluctuations, like ATP depletion, vanadate or fluoride, also inhibited endovesiculation whereas activation of PKC, known to decrease cytoskeleton association and increase membrane fluctuations, also enhanced endovesicle formation. This indicates that endovesicle formation and membrane fluctuations are modulated by the same cytoskeleton-regulated membrane properties. Further, acanthocytic erythrocytes of chorea acanthocytosis (ChAc) patients that lack the VPS13A/chorein protein - likely a crucial organizer at the erythrocyte cytoskeleton/membrane interface - showed a strong decrease in chlorpromazine-induced endovesiculation. The responses of ChAc erythrocytes to effectors of endovesiculation were similar to that of control erythrocytes, yet at drastically reduced levels. This suggests a more rigid and less dynamic interaction at the membrane-cytoskeleton interphase of ChAc erythrocytes.
authors.affiliation: Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Oberwagner
authors.affiliation: Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sauer
authors.affiliation: Department of Neurology, Technische Universität Dresden, German Centre for Neurodegenerative Diseases (DZNE), Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermann
authors.affiliation: Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Prohaska
authors.affiliation: Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.
authors.forename: Ernst W
authors.initials: EW
authors.lastname: Müllner
authors.affiliation: Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria. Electronic address: ulrich.salzer@univie.ac.at.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Salzer
mesh_terms: D002746:Chlorpromazine / Q000008:administration & dosage* / Q000009:adverse effects; D022162:Cytoplasmic Vesicles / Q000378:metabolism* / Q000473:pathology; D003599:Cytoskeleton / Q000378:metabolism* / Q000473:pathology; D004910:Erythrocyte Membrane / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D054546:Neuroacanthocytosis / Q000097:blood* / Q000188:drug therapy; D033921:Vesicular Transport Proteins / Q000172:deficiency*
chemical_list: C429654:VPS13A protein, human; D033921:Vesicular Transport Proteins; D002746:Chlorpromazine