title: Ablation of the Kell/Xk complex alters erythrocyte divalent cation homeostasis.
abstract: XK is a putative transporter of unknown function that is ubiquitously expressed and linked through disulfide bonds to Kell protein, an endothelin-3 (ET-3)-converting enzyme. We generated three knockout (KO) mice that lacked either Xk, Kell or both proteins and characterized erythrocyte cation levels, transport and hematological parameters. Absence of Xk or Kell was accompanied by changes in erythrocyte K(+), Mg(2+), Na(+) and Ca(2+) transport that were associated with changes in mean cellular volume and corpuscular hemoglobin concentration mean. Baseline Ca(2+)-ATPase activity was undetected in erythrocytes from all three mouse types but was restored upon pre-incubation with ET-3. Consistent with these alterations in Ca(2+) handling, we observed increased Gardos channel activity in Kel and Xk KO mice. In addition Kel deletion was associated with increased Mg(2+) permeability while Xk deletion blocked Na/Mg exchanger activity. Our results provide evidence that cellular divalent cation regulation is functionally coupled to the Kell/XK system in erythrocytes and loss of this complex may contribute to acanthocytosis formation in McLeod syndrome.
authors.affiliation: Department of Laboratory Medicine, Boston Children's Hospital, Department of Pathology Harvard Medical School, Boston, MA, USA. Alicia.rivera@childrens.harvard.edu
authors.forename: Alicia
authors.initials: A
authors.lastname: Rivera
authors.forename: Siok Yuen
authors.initials: SY
authors.lastname: Kam
authors.forename: Mengfatt
authors.initials: M
authors.lastname: Ho
authors.forename: Jose R
authors.initials: JR
authors.lastname: Romero
authors.forename: Soohee
authors.initials: S
authors.lastname: Lee
mesh_terms: D000012:Abetalipoproteinemia / Q000097:blood / Q000235:genetics; D000050:Acanthocytes; D026921:Amino Acid Transport Systems, Neutral / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017920:Antiporters / Q000097:blood; D002118:Calcium / Q000097:blood; D000252:Calcium-Transporting ATPases / Q000097:blood; D002413:Cations, Divalent / Q000097:blood*; D019334:Endothelin-3 / Q000494:pharmacology; D004911:Erythrocyte Volume; D004912:Erythrocytes / Q000378:metabolism*; D040181:Genetic Diseases, X-Linked / Q000097:blood / Q000235:genetics; D006461:Hemolysis / Q000235:genetics; D006706:Homeostasis; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000097:blood; D017136:Ion Transport; D007626:Kell Blood-Group System / Q000235:genetics / Q000502:physiology*; D008274:Magnesium / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D054546:Neuroacanthocytosis; D011188:Potassium / Q000097:blood; D017466:Receptors, Endothelin / Q000097:blood; D012964:Sodium / Q000097:blood
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D017920:Antiporters; D002413:Cations, Divalent; D019334:Endothelin-3; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D007626:Kell Blood-Group System; D046912:Multiprotein Complexes; D017466:Receptors, Endothelin; C498286:Xkh protein, mouse; C098996:endothelin-3 receptor; C046250:sodium-magnesium antiporter; D012964:Sodium; D000252:Calcium-Transporting ATPases; D008274:Magnesium; D011188:Potassium; D002118:Calcium