Structure of the Ion Channel

In each section on the different ion channels, some unresolved issues and future directions will be addressed. In general, little is known about the precise molecular structures of the ion channels (e.g., K+ channels) in smooth muscle and our knowledge of endogenous agents as well as key signal transduction pathways that may modulate smooth muscle ion channels is far from complete. Further, as indicated previously, the modulation and expression of ion channels vary with the type of, and even within (e.g., large versus small arteries), smooth muscle. Studies on K+ channels in nonvascular types of smooth muscle will be discussed if similar material from arterial smooth muscle is limited. 

Figure 41-9. Diagrammatic representation of the structures of two ion channels. The Roman numerals indicate the four subunits of each channel and the Arabic numerals the a-helical transmembrane domains of each subunit. The actual pores through which the ions pass are not shown but are formed by apposition of the various subunits. The specific areas of the subunits involved in the opening and closing of the channels are also not indicated. (After WKCatterall. Modified and reproduced from Hall ZW An Introduction to Molecular Neurobiology. Sinauer, 1992.)...

Why should we study the structural properties of the channel macromolecules themselves Although biophysical techniques define the functional properties of voltage-sensitive ion channels clearly, it is important to relate those functional properties to the structure of the channel proteins. We focus first on the discovery of the ion channel proteins, in which three different experimental approaches were used... 

Ion channels are large proteins which form pores through the neuronal membrane. The precise structure and function of the ion channels depend on their physiological function and distribution along the dendrites and cell body. These include specialized neurotransmitter-sensitive receptor channels. In addition, some ion channels are activated by specific metal ions such as sodium or calcium. The structure of the voltage-dependent sodium channel has been shown to consist of a complex protein with both a hydrophilic and a hydrophobic domain, the former domain occurring within the neuronal membrane while the latter domain occurs both inside and outside the neuronal membrane. 

Fig. 16.2. The elementary processes at a chemical synapse, a) In the resting state, the nenrotrans-mitter is stored in vesicles in the presynaptic cell, b) An arriving action potential leads to influx of Ca into the presynaptic cell. Consequently, the vesicles fuse with the presynaptic membrane and the neurotransmitter is released into the synaptic cleft, c) The neurotransmitter diffuses across the synaptic cleft and binds to receptors at the surface of the postsynaptic cell. Ion channel and receptor form a structural unit. The ion channel opens and there is an influx of Na ions into the postsynaptic cell. Recychng takes place in the presynaptic cell and the vesicles are reloaded with neurotransmitter.

Fig. 16.4. Subunit structure of voltage-con-trolled ion channels. The subunit structure of various voltage-controlled ion channels is shown in schematic form with nomenclature of the different subunits. Phosphorylation sites (P) in the cytoplasmic part are also shown, as well as glycosylation sites (Y) in the extracellular part of the ion channels.

The function of the ion channels is also regulated by phosphorylation of intracellular structural elements. The biochemical basis of this regulation is poorly understood. 

Fig. 16.12. Subunit structure of the acetylcholine receptor, a) The acetylcholine receptor has the subunit structure 02 7 - The four transmembrane elements Ml—M4 are shown for the y subunit. The binding sites for acetylcholine (ACh) are located on the a-subunits. b) It is assumed that the inner wall of the ion pore is formed by M2 helices of the five subunits, c) Postulated configuration of the M2 helices in the narrowest region of the ion channel. In the closed state, five leucine residues (one per subunit) lie in the ion channel and hinder passage of ions. Above and below the block, there are negatively charged residues that serve as prefilters for ion passage.

Figure 2.7 Cutaway stereoview of the X-ray crystal structure of the K+ channel of Streptomyces lividans. The upper and lower ends of the channel are regions of high negative charge density while the central portion comprises hydrophobic amino acid side chains. Positively charged regions are on the outer surface, while the spheres represent K+ ion positions. (Reproduced with permission from [2] MacKinnon).

The first high resolution crystal structure of an ion channel (3.2 A resolution), the potassium channel KscA from a bacteria, was provided by... 

A number of different X-ray structures of bacterial potassium channels reveal the detailed atomic picture of the pore-forming part, helices S5 and S6 [9]. KcsA, which is crystallized in the closed conformation, has an overall structure similar to an inverted teepee [9a], Four identical subunits surround the ion-conducting pathway (Figure 8.2). Each subunit contains two full transmembrane helices, S5 and S6, as well as the P loop. The S6 helices line the central cavity, whereas the S5 helices are involved in interactions with the lipid environment. In the closed channel conformation the transmembrane helices meet at the cytosolic side to block the ion conduction path. In the open conformation of the channel, the S6 helix kinks at a conserved glycine residue to open the ion conduction path, as shown in the structure of the bacterial channel MthK [10], The ion conduction path is formed by the selectivity filter and the large water-filled central cavity. 

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