Voltage sensitivity

Figure C3.6.9 Spiral electrochemical wave in dog epicardial muscle visualized using a voltage-sensitive dye. Reproduced by pennission from Pertsov and Jalife [41].

FIGURE 17.26 The o i-subuiiit of the t-tubule Ca" chainiel/DHP receptor contains six peptide segments that may associate to form the Ca" channel. This Ca" channel polypeptide is homologous with the voltage-sensitive Na channel of neuronal tissue. 

Stimulation of mAChRs also results in the activation or inhibition of a large number of ion channels [5]. For example, stimulation of Mi receptors leads to the suppression of the so-called M current, a voltage-dependent Recurrent found in various neuronal tissues. M2 receptors, on the other hand, mediate the opening of cardiac Ikcacii) channels, and both M2 and M4 receptors are linked to the inhibition of voltage-sensitive calcium channels [5]. 

This subfamily including the large- (BKCa), intermediate-(IKca), and small-conductance (SKCa) Ca2+-activated K + channels are activated by increases in intracellular free Ca2+ concentration. The opening of DCca and SKCa channels are less voltage-dependent, whereas the activation of BKCa channel has steep voltage sensitivity. 

Saxitoxin (STX) is a toxin which is found in marine microorganisms. It is most likely synthesized by bacteria which live in symbiosis with dinoflagellates, a component of phytoplankton. Through the marine food chain, it can lead to poisoning of humans. The mechanism of toxicity of saxitoxin is vety similar to that of tetrodotoxin. Saxitoxin binds from the outside of the membrane to various forms of voltage-sensitive Na+channels and blocks the channel in an activation state-independent manner. 

All transmitters (except NO) are released by the following cascade arrival of the nerve action potential at the terminal - opening of voltage-sensitive Ca2+... 

Synaptic vesicles are the organelles in axon terminals that store neurotransmitters and release them by exocytosis. There are two types, the large dense-core vesicles, diameter about 90 nm, that contain neuropeptides, and the small synaptic vesicles, diameter about 50nm, that contain non-peptide transmitters. About ten vesicles per synapse are docked to the plasma membrane and ready for release, the readily releasable pool . Many more vesicles per synapse are stored farther away from the plasma membrane, the resting pool . When needed, the latter vesicles may be recruited into the readily releasable pool. Neuronal depolarization and activation of voltage-sensitive Ca2+... 

Tetrodotoxin (TTX) is a toxin derived from bacteria which is concentrated in the gonads and liver of certain pufferfishes (fugu). Similar to saxitoxin, tetrodotoxin is a very potent blocker of most voltage-sensitive Na+ channels. 

Ligand regulation. There are no clear cases for smooth muscle where a first or a second messenger molecule binding to a Ca channel of any type causes an activation (opening) of the channel or a shift of the voltage sensitivity. However, these remain as viable possible modes of regulation. 

Brevetoxins Unique Activators of Voltage-Sensitive Sodium Channels... 

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... 

Another potentially paralytic conotoxin was recently described this was a peptide purified from Conus geographus venom, which like / -conotoxin appeared to target to voltage-sensitive Na channels. However, the structure of "conotoxin GS" [nomenclature of Yanagawa et al. (J7)] was less homologous to / -conotoxins than to the w-conotoxins, which are Ca channel blockers. The same peptide was purified and characterized using a different assay, the induction of highly aberrant behavior upon ic injection of mice (L. J. Cruz, unpublished data). 

This channel is voltage-sensitive — that is, its activity is increased when the membrane is depolarised. Thus, the channel opens very infrequently and for very short periods at —50mV, but opens more frequently and for longer times at —30mV. This activity is expressed by the open probability (Po), that is, the probability that, at any given time, the channel is open (or, in other words, the proportion of time the channel spends in the open state). In the example illustrated, Pq was 0.02 at —50 mV and 0.27 at —30mV. 

Although there is no evidence that the neuronal degeneration of AzD results, as in cardiovascular ischaemia, from the excitotoxicity of increased intracellular Ca +, some calcium channel blockers have been tried in AzD. They have had little effect but surprisingly a pyrrolidone derivative nefiracetam, which opens L-type voltage-sensitive calcium channels (VSCCs) reduces both scopolamine- and )S-amyloid-induced impairments of learning and memory in rats (Yamada et al. 1999). This effect can be overcome by VSCC antagonists, but nefiracetam has not been tried in humans. 

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