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“The following remarks consist partially of matter of fact, and partially of opinion. The former will be permanent; the latter must vary with the detection of error, or the improvement of knowledge. I hazard them with diffidence, and hope they will be examined with candour.” These declarations, which stem from the famous book “An Account of the Foxglove and some of its Medical Uses” by physician William Withering in 1785 in which he introduced preparations from digitalis leaves in the therapy of dropsy (cardiac failure), are cited here by the senior author because of his awareness of the difficulties in presenting a balanced report on his life‐long research project on the further development of digitalis. His decision to devote himself to digitalis research originated at the bedside, when as a physician he experienced the grim final stages of cardiac failure in which no real help for the patients is possible. Unfortunately, his research project did not fit into the research program decreed by the Ministry of Science of the German Democratic Republic, so that he was ordered to stop the digitalis project in favor of biomembrane studies. Fortunately, he got round the ban simply by labeling the digitalis‐like acting steroids as probes for the cell membrane‐located Na+/K+‐transporting ATPase which he had just recognized as the digitalis target (receptor) enzyme. These and other ventures by the authors are collated here for the first time. The aim of this review is to foster straightforward research for solving a major challenge: the development of steroidal drugs for the prevention and cure of cardiac failure.

Since 1985, several research groups have shown that a number of amino acids in the catalytic a-subunit of Na+/K +-ATPase more or less strongly modulate the affinity of a digitalis compound like ouabain to the enzyme. However, scrutiny of these findings by means of chimeric Na+/K+-ATPase constructs and monoclonal antibodies has recently revealed that the modulatory effect of most of these amino acids does not at all result from direct interaction with ouabain, but rather originates from longrange effects on the properties of the digitalis binding matrix. Starting from this knowledge, the present review brings together the various pieces of evidence pointing to the conclusion that the interface between two interacting a-subunits in the Na+/K+-ATPase protodimer (c~/3)2 provides the cleft for inhibitory digitalis intercalation.Key words: Na+/K+-transporting ATPase; Digitalis receptor; Binding cleft; Location; Property Na*/K+-ATPase is a complex of two catalytic ~-subunits and two catalytically inert fl-subunits, and a number of lipid molecules incorporated into the lipid bilayer of the plasma membrane. The cc-subunit contains about 1,012 amino acids. From the primary sequence, hydropathy analysis has been used to compute the local hydrophobicity and predict single-spanning s-helical segments that are long enough to traverse a 40 membrane (approximately 20 amino acids). The most recent 'working' model of the membrane topology of the enzyme, presented by Askew and Lingrel [14], comprises ten transmembrane segments (H1-H10) linked by five extracellularly disposed loops. Since the membrane topology models are constantly being revised to accommodate new findings, none of the defensible models (cf. Sweadner and Arystarkhova [15]) will be explicitly invoked here. Outcome of various attempts to identify the amino acids involved in the digitalis receptor site

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