Voltage-gating channel model

Figure 7. Voltage-gating channel model of alamethicin proposed by Fox and Richards (77). On the left is the structure for the helical bundle partially inserted in the absence of an applied voltage. The C-terminal residues are shown as helical ribbons that indicate extended random coil structures, or as cork-shaped a-helical structures partially buried on the surface of the membrane. The middle structure is an intermediate produced by application of voltage, and the right panel represents the open state that traverses the membrane. (Reproduced with permission from reference 77. Copyright 1982 Macmillan...

Numerous structural classes of potassium ion channels have been discovered. The six transmembrane domain proteins include voltage-gated channels (Kv), and Ca2+ activated K+ channels (Kca). However, there are also proteins with 2 transmembrane domains and 7 transmembrane domains [3]. The most widely studied potassium channel of relevance to toxicity and therefore the interests of the pharmaceutical industry to date appears to be Kv 11.1, the human ether-a-go-go-related gene (hERG), as is described in more detail below. Some computational modeling of other potassium channels is also addressed. 

Blank Electrochemical Model of Voltage-Gated Channels... 

Calcium channels have been shown to play a role in epilepsy as well [23]. Currently used antiepileptic drugs exhibit a wide spectrum of activity, including modulation of voltage-gated sodium and calcium channels. T-type calcium channels have been demonstrated to play an important role in absence epilepsy, a specific form of epilepsy characterized by brief lapses in consciousness correlated with spike-and-wave discharges in the electroencephalogram [14,24-28]. Ethosuximide 1 has been shown to block T-type calcium channels and is used clinically to treat absence epilepsy [25]. Several selective small-molecule T-type calcium channel antagonists have demonstrated efficacy in rodent epilepsy models (vide infra). 

Shrivastava IH, Durell SR, Guy FIR (2004) A model of voltage gating developed using the Kvap channel crystal structure. Biophys J 87 2255-2270... 

O Reilly AO, Khambay BP, Williamson MS, Field LM, Wallace BA, Davies TG (2006) Modelling insecticide-binding sites in the voltage-gated sodium channel. Biochem J 396 255-263... 

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