Dihydropyridine receptors in muscle are voltage-dependent but most are not functional calcium channels

Abstract

1,4-Dihydropyridines are a new class of compounds believed to bind specifically and with high affinity to voltage-dependent calcium channels^1–5. They may be the first example of a ligand of use in the extraction^1,2 and purification³ of the Ca channel. Although Ca channels and dihydropyridine receptors are found in many tissues, the richest and most convenient source is skeletal muscle⁴. Functionally, 1,4-dihydropyridines such as nifedipine and nitrendipine block Ca channels^6–11; this effect is believed to form the basis for their clinical importance as Ca antagonists in relaxing vascular smooth muscle⁶. But where currents through Ca channels can be measured directly^7–10, the block has required 100–1,000 times higher concentrations of dihydropyridine than necessary for the saturation of dihydropyridine binding sites^1,5. This discrepancy has remained unresolved because the study of pharmacological effects on Ca channels has required intact cells, while it has been difficult to investigate binding in other than cell-free preparations. Here we describe a method for measuring dihydropyridine binding to intact skeletal muscle and we compare our results with voltage-clamp measurements of Ca-channel block. We conclude that less than a few per cent of the binding sites in skeletal muscle represent functional Ca channels, contrary to general belief.