Figure 1. Ca2+ channel conformational states as potential drug targets.

Figure 1

Ca2+ channel conformational states as potential drug targets. A) Voltage-gated Ca2+ (Cav) channels reside in closed (resting), activated (open) and several inactivated (I) states (i.e., Ca2+-dependent inactivation [I-Ca], fast [I-fast] and slow [I-slow] voltage-dependent inactivation). Transitions to I-fast and I-slow occur upon membrane depolarizations, transitions to I-Ca are dependent on the intracellular Ca2+ concentration. Negative shifts of the membrane potential promote transitions of open and/or inactivated channels to the resting state. It is hypothesised that some Ca2+ channel blockers (e.g., DHPs) interact with an inactivated channel conformation.20,21 Recent data from Berjukow et al34 and Sokolov et al32 suggest that transitions to the fast voltage-dependent inactivated state (I-fast) are of particular importance for the drug-channel interaction. B) Cav2.1 inactivation is affected by β-subunit composition and point mutations introduced into the α1-subunit. Representative barium and calcium currents through a Cav1.2 construct composed of β1a- or β2a-subunits32 and currents through a mutant Cav1.2(β1a) where a single valine in segment IVS6 was substituted by alanine (V1477A34). Holding potential -80 mV, test pulses to 20 mV. C) Putative topology of a Cav channel a1-subunit. β-Subunits modulate Cav channel properties by interacting with the intracellular linker between domains I and II, carboxy and amino terminus (highlighted in black).6 D) Segments IIIS5, IIIS6 and IVS6 of Cav1.2. The putative drug-binding determinants (according to refs. 5, 40) are indicated as black dots (L-type channel numbering here and further on according to α1C-II; accession number: M67515). Amino acids that have been shown to modulate channel inactivation are shown in white circles.

From: Calcium Channel Block and Inactivation: Insights from Structure-Activity Studies

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