Peptidyl Inhibitors of Shaker-Type Kv1 Channels Elicit Twitches in Guinea Pig Ileum by Blocking Kv1.1 at Enteric Nervous System and Enhancing Acetylcholine Release

  1. Guilherme Suarez-Kurtz1,1,2,
  2. Rosane Vianna-Jorge3,
  3. Bianca F. Pereira2,2,
  4. Maria Luisa Garcia4 and
  5. Gregory J. Kaczorowski4
  1. 1Coordenação de Pesquisa, Instituto Nacional de Câncer (G.S.K.), and 2Departamentos de Bioquı́mica (G.S.K., B.F.P.) 3e Farmacologia (R.V.J.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; and 4Department of Membrane Biochemistry and Biophysics (M.L.G., G.J.K.), Merck Research Laboratories, Rahway, New Jersey

    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

    • 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

    • ↵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.

    • ↵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.
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    1. JPET June 1, 1999 vol. 289 no. 3 1517-1522
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