Sodium channels 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. 

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). 

Fig. 13. Location of calcium ion binding site in the Gramicidin A channel —. For comparison, the sodium ion binding site is included...

Poli MA, Mende TJ, Baden DG (1989) Brevetoxins, unique activators of voltage-sensitive sodium channels, bind to specific sites in rat brain synaptosomes. Mol Pharmacol 30 129-135 Pullaiah KC, Surapaneni RK, Rao CB, Albizati KF, Sullivan BW, Faulkner DJ, He CH, Clardy J (1985) Dictyoxetane, a novel diterpene from the brown alga Dictyota dichotoma from the Indian Ocean. J Org Chem 50 3665-3666... 

Poli, M.A. et al., Brevetoxins, unique activators of voltage-sensitive sodium channels, bind to specific sites in rat brain synaptosomes, Mol Pharmacol 30, 129, 1986. 

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.

The putative binding site for local anaesthetic molecules at the sodium channel has been identified as two amino acids in the sixth membrane-spanning segment of domain IV [2]. This binding site is located directly underneath the channel pore and can only be reached from the internal side of the membrane. Because local anaesthetics are applied exterior to the nerve fibre, they have to penetrate the axonal membrane before they can bind to the channel. 

TTX) and saxitoxin, which block the channel pore from the outer side. The difference in TTX sensitivity among the sodium channels is caused by a single amino acid difference in the P region of repeat I (phenylalanine or tyrosine in TTX-sensitive channels cysteine or serine in TTX-resistant channels). The S6 segments contribute to forming the inner pore of the channel and binding sites for local anesthetics. 

The saxitoxins function by binding to a site on the extracellular surface of the voltage-activated sodium channel, interrupting the passive inward flux of sodium ions that would normally occur through the channel while it is in a conducting... 

Research in this area advanced in the 1970 s as several groups reported the isolation of potent toxins from P. brevis cell cultures (2-7). To date, the structures of at least eight active neurotoxins have been elucidated (PbTx-1 through PbTx-8) (8). Early studies of toxic fractions indicated diverse pathophysiological effects in vivo as well as in a number of nerve and muscle tissue preparations (reviewed in 9-11). The site of action of two major brevetoxins, PbTx-2 and PbTx-3, has been shown to be the voltage-sensitive sodium channel (8,12). These compounds bind to a specific receptor site on the channel complex where they cause persistent activation, increased Na flux, and subsequent depolarization of excitable cells at resting... 

---