Charybdotoxin (CTX), a small, basic protein from scorpion venom, strongly inhibits the conduction of K ions through high-conductance, Ca2+-activated K + channels. The interaction of CTX with Ca2+-activated K + channels from rat skeletal muscle plasma membranes was studied by inserting single channels into uncharged planar phospholipid bilayers. CTX blocks K § conduction by binding to the external side of the channel, with an apparent dissociation constant of ---10 nM at physiological ionic strength. The dwelltime distributions of both blocked and unblocked states are single-exponential. The toxin association rate varies linearly with the CTX concentration, and the dissociation rate is independent of it. CTX is competent to block both open and closed channels; the association rate is sevenfold faster for the open channel, while the dissociation rate is the same for both channel conformations. Membrane depolarization enhances the CTX dissociation rate e-fold/28 mV; if the channel's open probability is maintained constant as voltage varies, then the toxin association rate is voltage independent. Increasing the external solution ionic strength from 20 to 300 mM (with K § Na +, or arginine +) reduces the association rate by two orders of magnitude, with little effect on the dissociation rate. We conclude that CTX binding to the Ca2+-activated K § channel is a bimolecular process, and that the CTX interaction senses both voltage and the channel's conformational state. We further propose that a region of fixed negative charge exists near the channel's CTX-binding site. INTRODUGTIONThe high-conductance, Ca~+-activated K + channel is present in the plasma membranes of many types of cells, both excitable and inexcitable (Latorre, 1086). Its

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The Buddhist teaching known in English as the four noble truths is most often understood as the single most important teaching of the historical buddha, Siddhartha Gautama, who taught in northern India during the 5th century bce. —Sanskrit duḥkha and Pali dukkha (pain), samudayo (arising), nirodho (ending), and maggo (path) or dukkhanirodhagāminī paṭipadā (way leading to the ending of pain)—are recorded in the languages of Pali and Sanskrit in the different Buddhist canons, and the literary traditions have been very consistent in how they remember the teaching. These teachings are explained in the Sutta on the Turning of the Dhamma Wheel (Dhamma-cakka-ppavattana Sutta in Pali) and in a handful of different formulations in different suttas, abhidhamma analysis, and in the vinaya sections of the canonical texts. Despite the widespread awareness of the four truths, the complexities associated with this teaching are not usually recognized. While the bulk of the scholarship on the four noble truths analyzes them as they appear in the Pali canon, recent scholarship traces them through Buddhist canons that are extant in the Chinese Tripitaka.

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