Calcium Channel Blocking Agents


Voltage‐dependent Ca2+ signalling in electrically excitable cells is controlled by the activity of different types of voltage‐gated Ca2+ channels. Selective channel blockers are important not only for treating cardiovascular diseases but also as pharmacological and biochemical tools for defining different channel types, determining their molecular structure, cloning channel subunits and refining their physiological and pathophysiological roles.

Keywords: calcium channel blockers; drug binding domains

Figure 1.

Structure of voltage‐gated Ca2+ channels. (a) α1 subunits form the pore of all voltage‐gated Ca2+ channels. Voltage‐gated Ca2+ channels can associate with accessory subunits (α2‐δ, β, γ) that control channel gating and modulation by various second messenger pathways. (b) Classical folding model of Ca2+ channel α1 subunits based on secondary structure predictions. Each homologous repeat (I–IV; helices 1–6) contains a pore motif (indicated in blue) that contributes to the formation of a single ion pore (P). This motif is conserved in other cation channels, including bacterial K+‐channels (panel e). In Ca2+channels, glutamate residues in the pore loops (S5–S6 linkers, red circles) comprise a Ca2+‐binding domain that serves as the selectivity filter. (c) Approximate position of the most important amino acid residues forming the DHP drug‐binding domain in repeats III and IV of L‐type α1 subunits (black circles). (d) In the folded structure, IIIS5, IIIS6 and IVS6 can form a multisubsite drug‐binding domain for DHP binding (triangle), for example. (e) Alternative model of the folding structure of a homologous α1 subunit repeat based on the X‐ray structure of a bacterial voltage‐gated K+‐channel. Voltage‐dependent gating is proposed to result in movement of the voltage‐sensor paddle towards the extracellular membrane surface (Jiang et al., ).

Figure 2.

Chemical structure of L‐type Ca2+ channel blockers. The amino acid sequence of Calciseptine is given in single‐letter code. Disulfide bridges are indicated.

Figure 3.

Structure of selective non‐L‐type channel blockers. (a) (+)‐ECN is a steroid with some selectivity for T‐type Ca2+ channels. Mibefradil also blocks high‐voltage‐activated Ca2+ channels. (b) The amino acid sequences of peptide toxins are given in single‐letter code; O, hydroxyproline; –, gaps for alignment; brackets indicate disulfide bond formation; *, amidated carboxyl terminus. (c) Proposed three‐dimensional structures of ω‐conotoxin GVIA and MVIIA based on NMR studies (PDB files 2CCO and 1OMG, respectively). Space‐filling structures of the peptides were aligned and colour‐coded according to Lew et al. using Raswin Molecular graphics Ver 2.6. Residues mediating N‐type Ca2+ channel affinity are coloured. Mutation of red residues reduces affinity >100‐fold. Mutation of orange and yellow residues reduces affinity >10‐fold.



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Further Reading

Deisseroth K, Mermelstein PG, Xia H and Tsien RW (2003) Signaling from synapse to nucleus: the logic behind the mechanisms. Current Opinion in Neurobiology 13: 354–365.

Fleckenstein A (1983) Calcium Antagonism in Heart and Smooth Muscle. New York: Wiley.

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Perez‐Reyes E (2003) Molecular physiology of low‐voltage‐activated t‐type calcium channels. Physiological Reviews 83: 117–161.

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Striessnig, Jörg, and Glossmann, Hartmut(Sep 2005) Calcium Channel Blocking Agents. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0004060]