K+ channel Structure

Figure 4. Schematic representation of the KcsA K+ channel structure. Two of the four subunits are shown the other two lie above and below the plain of the page. Each subunit is composed of the N- and C-terminated a-helices, the pore helix, and the loop containing the conserved G-Y-G sequence. The selectivity filter resides near the extracellular face of the membrane. Three positive ions are shown as they appear approximately in the crystal structure. Reproduced with author s permission from Dougherty, D. A. Lester, H. A. Angew. Chem., Int. ed. Engl. 1998, 37, 2330.

K+ Channel Structure-Activity Relationships and Mechanisms of Drug-Induced QT Prolongation... 

K+ CHANNEL STRUCTURE-ACTIVITY RELATIONSHIPS AND MECHANISMS OF DRUG-INDUCED QT PROLONGATION... 

All K channels are tetrameric molecules. There are two closely related varieties of subunits for K channels, those containing two membrane-spanning helices and those containing six. However, residues that build up the ion channel. Including the pore helix and the inner helix, show a strong sequence similarity among all K+ channels. Consequently, the structural features and the mechanism for ion selectivity and conductance described for the bacterial K+ channel in all probability also apply for K+ channels in plant and animal cells. 

The open channel has in most cases a selective permeability, allowing a restricted class of ions to flow,for example Na+, K+, Ca++ or Cl- and, accordingly, these channels are called Na+-channels, K+-channels, Ca -channels and Cr-channels. In contrast, cation-permeable channels with little selectivity reject all anions but discriminate little among small cations. Little is known about the structures and functions of these non-selective cation channels [1], and so far only one of them, the nicotinic acetylcholine receptor (nAChR, see Nicotinic Receptors), has been characterized in depth [2, 3]. The nAChR is a ligand-gated channel (see below) that does not select well among cations the channel is even permeable to choline, glycine ethylester and tris buffer cations. A number of other plasma... 

Concurrent with the progress in our1 understanding of molecular diversity, structure, and function of K+ channels, and their role in genetically linked and acquired... 

Several additional crystal structures of K+ channels have been solved since this article was written. Importantly,... 

Fig. 16.3 Perspective view of CU-2CuPO showing the channel structure where the salt lattice resides. The black lines highlight the bonding with Cu " (two-way sharing) and P " (three-way sharing) cations and the grey are 0. The grey dots represent K, Cs and Cl".

Historically the Shaker (Sh) K channel was the first K channel which was cloned and characterized [6-10]. Subsequently many more channel cDNAs and genes have been isolated and studied. Yet Sh channels remained in the forefront of channel research. The study of Sh channel mutants has provided the most thorough insight into structure-function relationships of K channels to date. I will first discuss in this chapter the primary sequences of voltage-gated channels. I will only use a few selected examples for discussion. As of this time, so many related K channel protein sequences have been published that it is not feasible to discuss all of them. Subsequently, I will describe in detail the present knowledge about functional K" " channel domains which are implicated in activation, inactivation and selectivity of the channel. 

Lehn 242 243) has described a solid phase model of a K+ channel based on the crown ether 37. The crystal structure of this inclusion complex reveals stacking of the crown ethers into vertical columns, empirical formula [2 37,2 K, 3 H20]2+, linked by water and potassium ions. The counter ions, empirical formula [K, 3 Br, 4 H20]2, comprise a polymeric chain running parallel to the columns. 

Na+ channels were identified by neurotoxin labeling and their primary structures were established by cDNA cloning 101 Ca2+ channels have a structure similar to Na+ channels 103 Voltage-gated K+ channels were identified by genetic means 103 Inwardly rectifying K+ channels were cloned by expression methods 103... 

Ca2+ channels [19] and functions as a tetramer of four separate subunits, analogous to the structure of Na+ and Ca2+ channels (Fig. 6-7B). Like the Na+ channels and the Ca2+ channels, the K+ channels have auxiliary subunits, which include intracellularly located p subunits as well as minK or minK-related subunits having a single transmembrane segment [19,20],... 

A third type of K+ channel, K2F, has a structure similar to two fused Kir subunits, and only two subunits are required to form a pore (Table 6-2) [39, 40]. These channels are often called leak channels or open rectifiers because they are continuously open. Like the Kir channels they are important in setting the resting membrane potential. Their activity is often regulated by kinases. 

---