Abstract
Potent and selective peptidyl blockers of theShaker-type (Kv1) voltage-gated potassium channels were used to determine the role of these channels in regulating the spontaneous motility of smooth muscle preparations. Margatoxin (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 abolished by tetrodotoxin (TTX, 0.5 μM), atropine (1 μM), hexamethonium (10 μM), or nifedipine (0.1 μM). It is proposed that blockade of Kv1 channels by MgTX, kaliotoxin, or the agitoxins increases excitability of intramural nerve plexuses in the ileum, promoting release of acetylcholine from excitatory motor nerve terminals. This, in turn, leads to Ca2+-dependent action potentials and twitching of the muscle fibers. MgTX does not induce twitches in several other guinea pig and/or rat vascular, genitourinary, or gastrointestinal smooth muscles, although small increases in spontaneous myogenic 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 of α-dendrotoxin, a selective blocker of Shaker Kv1.1 and 1.2 subtypes, or stichodactylatoxin, a peptide isolated from sea anemone that displays high affinity for Kv1.1 and 1.3, but not by charybdotoxin, which blocks Kv1.2 and 1.3 but not 1.1. The data taken together suggest that high-affinity blockade of Kv1.1 underlies the ability of MgTX, kaliotoxin, agitoxin-1, agitoxin-2, α-dendrotoxin, and stichodactylatoxin to elicit TTX-sensitive twitches in guinea pig ileum.
Footnotes
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Send reprint requests to: Dr. Guilherme Suarez-Kurtz, Instituto Nacional de Câncer, Coordenação de Pesquisa, Praça da Cruz Vermelha 23, Rio de Janeiro, RJ 20230-130, Brazil. E-mail: kurtz{at}inca.org.br
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↵1 G.S.K. is a Senior Investigator of Conselho Nacional de Desenvolvimento Cientı́fico e Tecnológico (Coordenação de Pesquisa), and work in his laboratory is supported by grants from CNPq, Financiadora de Estudos e Projetos, Ministério da Ciência e Tecnologia (Pronex), and Merck Research Laboratories.
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↵2 B.F.P. was supported by a student scholarship from CNPq.
- Abbreviations:
- Kv1 channels
- Shaker-type voltage-gated K+ channels
- maxi-K channel
- high-conductance Ca2+-activated K+ channel
- ChTX
- charybdotoxin
- IbTX
- iberiotoxin
- MgTX
- margatoxin
- KTX
- kaliotoxin
- AgTX1
- agitoxin-1
- AgTX2
- agitoxin-2
- α-DaTX
- α-dendrotoxin
- ShK
- stichodactylatoxin
- ShKDAP22
- Stichodactyla heliantus mutant toxin
- Received September 28, 1998.
- Accepted January 26, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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