Channel binding sites

This chapter briefly reviews the present understanding of the chemistry, origin, and distribution of the saxitoxins and methods for their detection. The second section of this chapter discusses studies on their pharmacology directed toward an understanding of the molecular basis for their strong, highly selective interaction with the sodium channel binding site. 

Differences in the equilibrium dissociation constant, K, for the binding of the various saxitoxins to the sodium channel binding site largely determine the differences in the potencies of the toxins in whole animal assays and in tissue preparations. 

The monocationic and dicationic adamantane derivatives have been used to investigate the topography of the channel binding sites of AMPA and NMDA receptors [135]. 

Nay Channel Binding Sites for Venom Neurotoxins and Drugs... 

Acidosis due to tissue h) xia favors local anesthetic toxicity because these drugs bind more avidly (or release less rapidly) from the sodium channel binding site when they are in the charged state. (Note that onset of therapeutic effect may be slower because charged local anesthetics penetrate the membrane less rapidly see text.) Hyperkalemia depolarizes the membrane, which also favors local anesthetic binding. Oxygenation reduces both acidosis and hyperkalemia. The answer is (D). 

Choudhary G, Shang L, Li X, Dudley SC Jr (2002) Energetic localization of saxitoxin in its channel binding site. Biophys J 83 912-919... 

Bolshakov, K.V., Tikhonov, D.B., Gmiro, V.E., and Magazanik, L.G. Different arrangement of hydrophobic and nucleophilic components of channel binding sites in N-methyl-d-aspartate and AMPA receptors of rat brain is revealed by channel blockade. Neurosci Lett 2000, 291 101-104. 

The absorption of sulfonylureas from the upper gastrointestinal tract is faidy rapid and complete. The agents are transported in the blood as protein-bound complexes. As they are released from protein-binding sites, the free (unbound) form becomes available for diffusion into tissues and to sites of action. Specific receptors are present on pancreatic islet P-ceU surfaces which bind sulfonylureas with high affinity. Binding of sulfonylureas to these receptors appears to be coupled to an ATP-sensitive channel to stimulate insulin secretion. These agents may also potentiate insulin-stimulated glucose transport in adipose tissue and skeletal muscle. 

An important characteristic of both classes of ion channel is that they possess multiple dmg binding sites (Table 2). Many of the channel-active dmgs have achieved particular therapeutic importance, including, for example, the Ca " antagonists, widely used for a number of cardiovascular disorders. 

Fig. 15. Drug binding sites associated with the GABA receptor—channel complex where (— -) represents the carbon backbone of GABA agonists.

The binding site is located at the tip of the subunit within the jelly roll structure (Figure 5.23). The sialic acid moiety of the hemagglutinin inhibitors binds in the center of a broad pocket on the surface of the barrel (Figure 5.24). In addition to this groove there is a hydrophobic channel that can accomodate large hydrophobic substituents at the C2 position of sialic acid (Figures 5.22 and 5.24). 

Figure 12.10 Diagram showing two subunits of the channel, illustrating the way the selectivity filter is formed. Main-chain atoms line the walls of this narrow passage with carbonyl oxygen atoms pointing into the pore, forming binding sites for ions. (Adapted from D.A. Doyle et al., Sdence 280 69-77, 1998.)...

As defined in Fig. BA, the quantity 2d in Equation 4 is the total length from one side to the other of the channel and at is the distance from the binding site to the central barrier. 

Fig. 8. A. Free energy profile for Na+ movement through the malonyl Gramicidin channel. Calculated using Eyring rate theory and the locations of binding sites in the channel.

Fig. 10. Calculated sodium ion single channel currents for the malonyl Gramicidin channel and comparison with experimental data points using four different models all of which fit the data well but only one of which, B., is correct. The point to be made is that both the independent determination of rate constants and of the binding site locations are required.

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