Receptor sodium channel

Answer Bupivacaine use for local anesthesia of this type is very safe and commonly done. However, SOMETIMES inadvertent vascular injection results in a large amount of anesthetic in the systemic circulation. Because the heart is beating, the excitable tissue in the heart is being depolarized repetitively. Local anesthetics bind to rapidly depolarizing tissues more than tissues at rest (frequency-dependent block). Also, bupivacaine has a long duration of action because of its long residence time at receptors (sodium channel). Thus, this combination of factors contributed to the catastrophic outcome of this case. Had the same case involved lidocaine, the resuscitation would have likely been successful. 

CFTR has a single-channel conductance of about 8 pS. It is present in the apical membranes of many epithelia. Its mutation leads to the potentially lethal disease cystic fibrosis. In addition to acting as a chloride channel, CFTR is also thought to regulate, e.g., the epithelial sodium channel ENaC, a molecularly unknown outwardly-rectifying chloride channel, and possibly also potassium channels and water channels. Some of these potential regulatory processes, however, are controversial. CFTR also acts as a receptor for bacteria. 

Hirschsprung s disease have ETB receptor mutations). The lack of ET-3/ETB receptor results in the absence of parasympathic ganglionic neurons in the myenteric plexus (Auerbach). Mice with an ET-3/ETB receptor disruption die within 2 weeks after birth. In transgenic mice, in which the expression of the ETB receptor is driven by the dopamine (3-hydroxylase promoter, normal myenteric plexus are present and no enteric disorder develops. These mice, however, show a salt-sensitive hypertension, which can be efficiently treated with amiloride, indicating that ETB receptors are involved in the regulation of natriuresis via the amilorid-sensitive sodium channel ENaC. 

Several diseases involving dysregulation of MR function have been described although most of them are not causatively linked to the receptor itself. Pseudohypoaldosteronism for example is a syndrome of mineralocorticoid resistance characterized by urinary salt loss and dehydration. However, only very rarely mutations in the MR gene have been found in these patients so far. In most cases, this syndrome appears to be linked to defects in the subunits of the amiloride-sensitive sodium channel ENaC, a major target of mineralocorticoid action in the kidney. 

Turning now to chemical attack, many predators immobilize their prey by injecting toxins, often neurotoxins, into them. Examples include venomous snakes, spiders, and scorpions. Some spider toxins (Quick and Usherwood 1990 Figure 1.3) are neurotoxic through antagonistic action upon glutamate receptors. The venom of some scorpions contains polypeptide neurotoxins that bind to the sodium channel. 

Note NaCh = sodium channel RF = resistance factor, which is LDjq resistant strain/LDjQ susceptible strain GABA = gamma amino butyric acid receptor PBO = piperonyl butoxide. 

FIGURE 5.4 Sites of action of organochlorine insecticides (a) sodium channel, (b) GABA receptor. (From Eldefrawi and Eldefrawi 1990. With permission.)... 

Resistance to DDT has been developed in many insect species. Although there are some cases of metabolic resistance (e.g., strains high in DDT dehydrochlorinase activity), particular interest has been focused on kdr and super kdr mechanisms based upon aberrant forms of the sodium channel—the principal target for DDT. There are many examples of insects developing resistance to dieldrin. The best-known mechanism is the production of mutant forms of the target site (GABA receptor), which are insensitive to the insecticide. 

Displacement Assay for TTX and STX. Davio and Fontelo (45) and Richie et al. (46) describe methods for detecting STX by measuring displacement of radiolabelled STX from brain membranes. The sensitivity of this assay is approximately 1 ng STX/ml. TTX can also be detected since STX and TTX share the same biological receptor on the sodium channel. 

Tamplin et. al. (54) observed that V. cholerae and A. hydrophila cell extracts contained substances with TTX-like biological activity in tissue culture assay, counteracting the lethal effect of veratridine on ouabain-treated mouse neuroblastoma cells. Concentrations of TTX-like activity ranged from 5 to 100 ng/L of culture when compared to standard TTX. The same bacterial extracts also displaced radiolabelled STX from rat brain membrane sodium channel receptors and inhibited the compound action potential of frog sciatic nerve. However, the same extracts did not show TTX-like blocking events of sodium current when applied to rat sarcolemmal sodium channels in planar lipid bilayers. 

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... 

These include nicotinic acetylcholine receptors, neuronal calcium channels, muscle sodium channels, vasopressin receptors, and iV-methyl-D-aspartate (NMDA) receptors. Some general features of the structure, function, and evolution of biologically active peptides isolated from Conus venom are presented. 

Over 40 different types of polypeptide toxins have been found in marine animals (i). Many of these toxins are exquisitely selective in their actions, affecting a single process or receptor at minute concentrations. So far the sea anemone and gastropod Conus) toxins have attracted the most attention as molecular probes of ion channels. In this chapter, we discuss several approaches which are being used to investigate, at the molecular level, the interactions of the sea anemone neurotoxic polypeptides with sodium channels. 

Non-NMDA ionotropic glutamate receptors (the majority sodium channel containing) can be subdivided into a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) (comprising cloned subunits GluRl ) and kainate (GluR5-7, KAl-2) preferring receptors, with native receptors most likely to comprise either homo- or heteromeric pentamers of these subunits. 

The last few years has seen an explosion in AEDs. Some of those mentioned above may fall by the wayside and others appear. At the time of writing, we could include felbamate, zonisamide oxcarbazepine and topiramate. They all appear to have a phenytoin-like action on sodium channels, although topiramate appears to also potentiate the action of GABA on GABAa receptors like the benzodiazepines but through a different site. 

Cohen-Armon M, Kloog Y, Henis YI, Sokolovsky M. Batrachotoxin changes the properties of the muscarinic receptor in rat brain and heart possible interaction(s) between muscarinic receptors and sodium channels. Proc Natl Acad Sci USA 1985 82 3524-3527. 

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