Toxins that affect voltage-dependent calcium channels.

At this time, there are five potential candidates for calcium channel specific toxins. All five of these toxins appear to affect the function of voltage-dependent calcium channels. Atrotoxin, beta-leptinotarsin-h and maitotoxin activate channels, whereas both taicatoxin and omega-conotoxin are inhibitors. Neither maitotoxin nor omega-conotoxin alters the binding of dihydropyridines to membranes derived from the cells upon which the toxins exert their effects. In contrast, both atrotoxin and taicatoxin inhibit the binding of dihydropyridines to ventricular membranes. It is not currently known whether beta-leptinotarsin-h affects the binding. The effects of maitotoxin and atrotoxin are blocked by dihydropyridines and verapamil. Direct binding studies with radiolabeled toxins have been performed only with omega-conotoxin, and the binding site density for this toxin appears to be at least one order of magnitude greater than the density of dihydropyridine binding sites in synaptosomes. Studies to examine the third and fourth criteria which we have listed (i.e. that the effects are not via a second messenger, or an enzyme activity) have not been reported for either beta-leptinotarsin-h or omega-conotoxin. Atrotoxin and taicatoxin, added outside a patch pipette, have no effects on calcium channels within the patch and are, therefore, probably not affecting calcium channels via a second messenger. Maitotoxin, however, affects the formation of inositol phosphates and, hence, could be affecting the channel indirectly. The fractions containing the toxic components atrotoxin and taicatoxin have no phospholipase or protease activity, and this is presumably true also for omega-conotoxin since it has been purified to homogeneity. Although all of the toxins have the potential to be important tools with which to study calcium channel structure and function, a number of experiments remain to be done in order to establish conclusively that these five toxins bind specifically to the voltage-dependent calcium channel. In conclusion, we would like to briefly mention why so much effort is being devoted to the search for these calcium channel specific toxins. Such a toxin would provide a very valuable tool in the study of calcium channels for a number of reasons. First, the toxin would be another ligand for the channel and, as such, would provide an alternative to organic ligands such as the dihydropyridines which are lipophilic and, in many tissues, have more than one binding site.(ABSTRACT TRUNCATED AT 400 WORDS)