ABSTRACT
The combination of patch-clamp techniques, ω-toxins, and molecular strategies has revealed a great heterogeneity of voltage-dependent Ca2+ channels in neurons. Peptide toxins derived from the venoms of marine snails Conus geographus (ω-conotoxin GVIA), Conus magus (ω-conotoxins MVIIA, MVIIC, and MVIID), as well as from Agelenopsis aperta spider venom (FTX, ω-agatoxin IVA) are powerful diagnostic pharmacological tools to discriminate between different subtypes of neuronal Ca2+ channels. Thus, so-called high-threshold-activated (HVA) Ca2+ channels are selectively recognized by ω-conotoxin GVIA and MVIIA (N-type), by low concentrations (nanomolar) of ω-agatoxin IVA (P-type), or by high concentrations of ω-agatoxin IVA (micromolar) or the ω-conotoxins MVIIC and MVIID (Q-type). L-type HVA Ca2+ channels present in neurons, cardiovascular tissues, skeletal and smooth muscle, and in endocrine cells are targetted by so-called organic Ca2+ antagonists such as the 1,4dihydropyridines (DHP) nifedipine or Bay K 8644, the benzylalkylamine verapamil, or the benzothiazepine diltiazem; they are also specifically blocked by snake toxins calciseptine and calcicludine. Wide-spectrum ω-toxins (ω-conotoxin MVIIC, ω-agatoxin IA, IIA, and IIIA) and organic compounds (flunarizine, dotarizine, cinnarizine, fluspirilene, R56865, lubeluzole) can block several classes of HVA Ca2+ channels, including the L-type. A neuronal R-type HVA channel seems to be resistant to all known toxins. Low-voltage-activated (LVA) channels (T-type) are blocked by 1-octanol, amiloride, and mibefradil, and are more sensitive to Ni2+ than to Cd2+; no toxins are known that recognize these channels.
