Calcium (Ca²⁺) channel blockers such as 1,4-dihydropyridines (DHPs), phenylalkylamines (PAAs), diltiazem (Dil) and mibefradil (Mib) exert their antiarrhythmic and antihypertensive action by restricting Ca2+ entry through voltage gated Ca²⁺ channels (Cav) into myocardial and smooth muscle cells. Most Cav are heterooligomeric protein complexes consisting of an α1-subunit, auxiliary β-, α2-δ and in some channels of an additional γ-subunit. The α1 subunits sense the membrane voltage, form the pore and define the basic pharmacological properties of the channels. They are composed of four homologous domains (I-IV) formed by six transmembrane segments (S1 – S6). β-subunits (β1,β2,β3,β4) modulate the channel inactivation and other gating properties. Site directed mutagenesis revealed a number of amino acids in S5 and S6 segments of L-channel domains III and IV that determine the inhibition by DHPs, PAAs and Dil. Some of these point mutations either enhance or impair channel inactivation and simultaneously increase or reduce channel inhibition by Ca²⁺ channel blockers. Fast inactivating L-channel mutants tend to be more efficiently inhibited by PAAs, Dil and Mib than slow-inactivating ones. A similar conclusion can be drawn from an analysis of the drug-sensitivities of Cav composed of either ‘accelerating’ (e.g. β1 or β3) or ‘decelerating’ β2a-subunits. Again, subunit compositions promoting faster channel inactivation increase the apparent drug sensitivity of most constructs. Thus slowing channel inactivation by point mutations in different parts of the α1-subunit has almost the same effect as coexpression of the ‘decelerating’ β2a. An open channel block mechanism can hardly explain the data. ‘Decelerating’ β2a-subunit increase the fraction of open channels which should enhance open channel inhibition but not decrease as observed. A modulated receptor concept would explain the correlation between inactivation and channel block by a higher affinity of PAAs, Dil and Mib to the inactivated state. The inactivation machinery of Cav is, however, sensitive to conformational changes in many different parts of the α1-subunit. Some inactivation determinants are located distant from the putative drug binding pocket in the pore. It is therefore more attractive to hypothesise that the numerous structural changes affect channel block in an indirect manner via a modulation of the inactivation mechanism and not by modulating drug-affinity. A possible scenario is a drug-inactivation-synergism where Ca2+ channel blockers and ‘accelerating’ β-subunits both stabilise an inactivated channel conformation (Hering, 2002). This hypothesis is not in contradiction with the notion that charged compounds access their receptor in the channel vestibule predominantly via the open channel conformation. Once these drugs interact with their binding site they are likely to promote inactivation. The β-subunit composition of Cav is likely to affects drug sensitivity of native cells. Cav in smooth muscle of the uterus and trachea are formed by β2- and β3-isoforms (Reimer et al. 2000). The ‘accelerating’ β3-subunit was found to associate with the α12.1 in the aorta which is expected to favour channel block in this tissue.