I.D.19 The Ca2+ Channel-forming Drug, Digitoxin (Digitoxin) Family

Heart failure drug digitoxin has been shown to induce calcium uptake into cells by forming transmembrane calcium channels (Arispe et al., 2008). Digitoxin and other cardiac glycosides are important, centuries-old drugs for treating congestive heart failure. Calcium is known to potentiate the toxicity of these drugs. Multimers of digitoxin are able to form calcium channels in pure planar phospholipid bilayers. These digitoxin channels are blocked by Al3+ and La3+ but not by Mg2+ or the classical l-type calcium channel blocker, nitrendipine. In bilayers, lipids affect the kinetics of the digitoxin channel activity, but not the cation selectivity. Antibodies against digitoxin neutralize digitoxin channels in both cells and bilayers. These digitoxin calcium channels may be part of the mechanism by which digitoxin and other active cardiac glycosides, such as digoxin, exert system-wide actions at and above the therapeutic concentration range.

The reactions catalyzed by digitoxin channels are:

Ca2+ (out) ⇌ Ca2+ (in)

cation (out) ⇌ cation (in)



Arispe, N., J.C. Diaz, O. Simakova, and H.B. Pollard (2008). Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels. Proc Natl Acad Sci U S A 105: 2610-5.

Bárány-Wallje, E., A. Andersson, A. Gräslund, and L. Mäler. (2004). NMR solution structure and position of transportan in neutral phospholipid bicelles. FEBS Lett. 567: 265-269.


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