Calciseptine, a Ca 2+ Channel Blocker, Has Agonist Actions on L-type Ca 2+ Currents of Frog and Mammalian Skeletal Muscle

Abstract

Calciseptine is a natural peptide consisting of 60 amino acids with four disulfide bonds. The peptide is a natural L-type Ca2+-channel blocker in heart and other systems, but its actions in skeletal muscle have not been previously described. The aim of this study is to characterize the effects of calciseptine on L-type Ca2+ channels of skeletal muscle and on contraction. Whole-cell, patch-clamp experiments were performed to record Ca2+ currents (I(Ca)) from mouse myotubes, whereas Vaseline-gap voltage-clamp experiments were carried out to record I(Ca) from frog skeletal muscle fibers. We found that calciseptine acts as a channel agonist in skeletal muscle, increasing peak I(Ca) by 37% and 49% in these two preparations. Likewise, the peptide increased intramembrane charge movement, though it had little effect on contraction. The molecular analysis of the peptide indicated the presence of a local, electrostatic potential that resembles that of the 1,4-dihydropyridine agonist Bay K 8644. These observations suggest that calciseptine shares the properties of 1,4-dihydropyridine derivatives in modulating the permeation of divalent cations through L-type channels.

Use of Venom Peptides to Probe Ion Channel Structure and Function

“…Calciseptine, a 60-aa four-disulfide bond peptide from black mamba Dendroaspis polylepsis polylepis venom, selectively inhibits dihydropyridine-sensitive cardiac L-type Ca 2ϩ channels but enhances L-type current in skeletal muscle (58). Calcicludine from the green mamba Dendroaspis angusticeps is a 60-residue three-disulfide bond peptide, resembling the dendrotoxins in structure, that blocks L-type Ca 2ϩ currents (59).…”

Peptide Neurotoxins That Affect Voltage-Gated Calcium Channels: A Close-Up on ω-Agatoxins

“…The peptide is a natural L-type calcium channel blocker in heart and smooth muscle cells. Recently, it was shown that calciseptine also acts as a calcium channel agonist in skeletal muscles, increasing calcium currents by around 40% [14], but it clearly does not affect N- nor T-type calcium channels. Observations in vitro and in vivo suggest that calciseptine shares the properties of 1,4-dihydropyridine derivatives in modulating the permeation of divalent cations through L-type calcium channels.…”

High-frequency fatigue of skeletal muscle: role of extracellular Ca2+

“…Our experiments with calciseptine, a drug that specifically blocks the α1C isoform of DHPR (de Weille et al 1991), seem to confirm this hypothesis, since it did inhibit the maximal tension induced during HFF (lower P hff in Table 1). A recent study on skeletal muscle showed that calciseptine did not affect twitch and tetanic tensions; however, this result was obtained in fasttwitch muscles (Garcia et al 2001) that do not express the a1C isoform (Pereon et al 1998). Our results also show that high concentration of extracellular Ca 2+ and the Ca 2+ ionophore A23187 did not affect peak tension, and this lack of effects suggests that the action of extracellular calcium is already maximal at physiological concentrations and that its action could only be reduced in Ca 2+ -free conditions.…”