Research directed towards discovering agents that enhance PKCa channel activity has followed two courses. One has been defining properties of the channel, as well as making use of toxins that are specific probes for characterizing channel binding sites and for isolating and purifying the channel. The second has been a study of the regulation of PKCa channels by guanine nucleotides. The following list summarizes the major findings and conclusions that have been drawn to date. (1) The high conductance (266 +/- 11.5 pS) PKCa channel of bovine aortic smooth muscle, which is the most abundant of the 3 kinds of PKCa channels observed, has properties very similar to high conductance PKCa channels found in other cell types. (2) Charybdotoxin (ChTX), a rather specific probe for PKCa channels, has been purified to homogeneity, characterized in terms of primary sequence, labeled with 125I, and used to study binding of ChTX to the receptor/channel complex. (3) A second high affinity toxin probe, with distinct biological activity, IbTX-I, has been purified to homogeneity, and its amino acid sequence determined. One of its distinct actions is to enhance channel activity at low nM levels, and to block the channel at concentrations above approximately 5 nM. (4) A number of vasodilators having the common action of increasing cytosolic cGMP levels, have been found to enhance PKCa channel activity in on-cell patches. (5) While all of the guanine nucleotides have been noted to enhance channel activity in excised patches at high concentrations (500 uM), only GMP is effective in the 10-100 uM range. (6) These data have led us to conclude that GMP is a physiological modulator of PKCa channels, and that it is most likely the second messenger for mediating the vasodilator-induced potentiation of channel activity.