title: Transport and pharmacological properties of nine different human Na, K-ATPase isozymes.
abstract: Na,K-ATPase plays a crucial role in cellular ion homeostasis and is the pharmacological receptor for digitalis in man. Nine different human Na,K-ATPase isozymes, composed of 3 alpha and beta isoforms, were expressed in Xenopus oocytes and were analyzed for their transport and pharmacological properties. According to ouabain binding and K(+)-activated pump current measurements, all human isozymes are functional but differ in their turnover rates depending on the alpha isoform. On the other hand, variations in external K(+) activation are determined by a cooperative interaction mechanism between alpha and beta isoforms with alpha2-beta2 complexes having the lowest apparent K(+) affinity. alpha Isoforms influence the apparent internal Na(+) affinity in the order alpha1 > alpha2 > alpha3 and the voltage dependence in the order alpha2 > alpha1 > alpha3. All human Na,K-ATPase isozymes have a similar, high affinity for ouabain. However, alpha2-beta isozymes exhibit more rapid ouabain association as well as dissociation rate constants than alpha1-beta and alpha3-beta isozymes. Finally, isoform-specific differences exist in the K(+)/ouabain antagonism which may protect alpha1 but not alpha2 or alpha3 from digitalis inhibition at physiological K(+) levels. In conclusion, our study reveals several new functional characteristics of human Na,K-ATPase isozymes which help to better understand their role in ion homeostasis in different tissues and in digitalis action and toxicity.
authors.affiliation: Institut de Pharmacologie et de Toxicologie de l'Université, Rue du Bugnon 27, CH-1005 Lausanne, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Crambert
authors.forename: U
authors.initials: U
authors.lastname: Hasler
authors.forename: A T
authors.initials: AT
authors.lastname: Beggah
authors.forename: C
authors.initials: C
authors.lastname: Yu
authors.forename: N N
authors.initials: NN
authors.lastname: Modyanov
authors.forename: J D
authors.initials: JD
authors.lastname: Horisberger
authors.forename: L
authors.initials: L
authors.lastname: Lelièvre
authors.forename: K
authors.initials: K
authors.lastname: Geering
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport; D002462:Cell Membrane / Q000201:enzymology; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes; D007700:Kinetics; D009865:Oocytes / Q000378:metabolism; D010042:Ouabain / Q000037:antagonists & inhibitors / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D018075:RNA, Complementary / Q000378:metabolism; D012964:Sodium / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D014981:Xenopus / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D018075:RNA, Complementary; D010042:Ouabain; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium