Peptidyl inhibitors of shaker-type K(v)1 channels elicit twitches in guinea pig ileum by blocking K(v)1.1 at enteric nervous system and enhancing acetylcholine release

Potent and selective peptidyl blockers of the Shaker-type (K(v)1) voltage-g ated potassium channels were used to determine the role of these channels i n regulating the spontaneous motility of smooth muscle preparations. Margat oxin (MgTX), kaliotoxin, and agitoxin-2 at 1 to 10 nM and agitoxin-1 at 50 to 100 nM induce twitches in guinea pig ileum strips. These twitches are ab olished by tetrodotoxin (TTX, 0.5 mu M), atropine(1 mu M), hexamethonium (1 0 mu M), o nifedipine (0.1 mu M). It is proposed that blockade of K(v)1 cha nnels by MgTX, kaliotoxin, or the agitoxins increases excitability of intra mural nerve plexuses in the ileum, promoting release of acetylcholine from excitatory motor nerve terminals. This, in turn, leads to Ca2+-dependent ac tion potentials and twitching of the muscle fibers. MgTX does not induce tw itches in several other guinea pig and/or rat vascular, genitourinary, or g astrointestinal smooth muscles, although small increases in spontaneous myo genic activity may be seen in detrusor muscle exposed to >30 nM MgTX. This effect is not reversed by TTX or atropine. The TTX- and atropine-sensitive twitches of guinea pig ileum are also induced by nanomolar concentrations o f alpha-dendrotoxin, a selective blocker of Shaker K(v)1.1 and 1.2 subtypes , or stichodactylatoxin, a peptide isolated from sea anemone that displays high affinity for K(v)1.1 and 1.3, but not by charybdotoxin, which blocks K (v)1.2 and 1.3 but not 1.1. The data taken together suggest that high-affin ity blockade of K(v)1.1 underlies the ability of MgTX, kaliotoxin, agitoxin -1, agitoxin-2, alpha-dendrotoxin, and stichodactylatoxin to elicit mt-sens itive twitches in guinea pig ileum.