Fig. 1. Intracellular access of the permanently charged quaternary phenylalkylamine (PAA)(–) qdevapamil (qDev) to its receptor site in L-type Ca2+ channels and in a PAA-sensitive mutant class A Ca2+ channel (α1A-PAA). a: Predicted transmembrane topologies of the voltage-gated Ca2+ channel α1-subunits of a PAA-sensitive class A mutant (α1A-PAA)(Ref. 5). An α-helical representation of the amino acid sequence of the sixth transmembrane segment (S6) of the fourth (IV) repeat (IVS6) is shown on the right. High-affinity determinants for PAA (Ref. 16) are indicated in red. Methionine (M1805, shown in deep blue) has a strong effect on inactivation and has been identified as an additional determinant for PAA (Ref. 5). b: The barium current (IBa) of α1A-PAA/ß1a, α2–δ Ca2+ channels5, 18 expressed in Xenopus oocytes was elicited by a train of pulses applied at 0.1 Hz from–80 to 20 mV. Traces were recorded in control conditions and after the extracellular (out)(50μM) or intracellular (in) application of (–) q-devapamil (qDev)(100μM). The inactivation of the current during a pulse and the use-dependent inhibition of IBa during a train of pulses are illustrated. c: IBa of the L-type α1Lh/ß1a, α2–δ channel15 during a train of pulses (see b) under control conditions and after the intracellular application of q-(–) devapamil (50μM). The experiments convincingly demonstrate that quaternary (membrane-impermeable) PAAs access their receptor site from the intracellular side upon channel activation. Fig. 1b reproduced with permission from Ref. 18.