Capsazepine, a synthetic vanilloid that converts the Na,K-ATPase to Na-ATPase

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    Yasser Ahmed Mahmmoud, Denmark
  • Institute of Biophysics
Capsazepine (CPZ), a synthetic capsaicin analogue, inhibits ATP hydrolysis by Na,K-ATPase in the presence, but not in the absence of K+. Studies with purified membranes revealed that CPZ reduced Na+-dependent phosphorylation by interference with Na+ binding from the intracellular side of the membrane. Kinetic analyses showed that CPZ stabilized an enzyme species that constitutively occluded K+. Low-affinity ATP interaction with the enzyme was strongly reduced following CPZ treatment; in contrast, indirectly measured interaction with ADP was much increased, which suggests that composite regulatory communication with nucleotides takes place during turnover. Studies with lipid vesicles revealed that CPZ reduced ATP-dependent digitoxigenin-sensitive 22Na+ influx into K+ loaded vesicles only at saturating ATP concentrations. The drug apparently abolishes the regulatory effect of ATP on the pump. Drawing on previous homology modeling studies of Na,K-ATPase to atomic models of sarcoplasmic reticulum Ca-ATPase and on kinetic data, we propose that CPZ uncouples an Na+ cycle from an Na+/K+ cycle in the pump. The Na+ cycle possibly involves transport through the recently characterized Na+-specific site. A shift to such uncoupled mode is believed to produce pumps mediating uncoupled Na+ efflux by modifying the transport stoichiometry of single pump units.
Udgivelsesdato: February 5
Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
Pages (from-to)1757
Number of pages1,761
StatePublished - 2008

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