XB-ART-56849
Toxins (Basel)
2020 Mar 21;123:. doi: 10.3390/toxins12030197.
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αM-Conotoxin MIIIJ Blocks Nicotinic Acetylcholine Receptors at Neuromuscular Junctions of Frog and Fish.
Rybin MJ
,
O'Brien H
,
Ramiro IBL
,
Azam L
,
McIntosh JM
,
Olivera BM
,
Safavi-Hemami H
,
Yoshikami D
.
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We report the discovery and functional characterization of αM-Conotoxin MIIIJ, a peptide from the venom of the fish-hunting cone snail Conus magus. Injections of αM-MIIIJ induced paralysis in goldfish (Carassius auratus) but not mice. Intracellular recording from skeletal muscles of fish (C. auratus) and frog (Xenopus laevis) revealed that αM-MIIIJ inhibited postsynaptic nicotinic acetylcholine receptors (nAChRs) with an IC50 of ~0.1 μM. With comparable potency, αM-MIIIJ reversibly blocked ACh-gated currents (IACh) of voltage-clamped X. laevis oocytes exogenously expressing nAChRs cloned from zebrafish (Danio rerio) muscle. αM-MIIIJ also protected against slowly-reversible block of IACh by α-bungarotoxin (α-BgTX, a snake neurotoxin) and α-conotoxin EI (α-EI, from Conus ermineus another fish hunter) that competitively block nAChRs at the ACh binding site. Furthermore, assessment by fluorescence microscopy showed that αM-MIIIJ inhibited the binding of fluorescently-tagged α-BgTX at neuromuscular junctions of X. laevis,C. auratus, and D. rerio. (Note, we observed that αM-MIIIJ can block adult mouse and human muscle nAChRs exogenously expressed in X. laevis oocytes, but with IC50s ~100-times higher than those of zebrafish nAChRs.) Taken together, these results indicate that αM-MIIIJ inhibits muscle nAChRs and furthermore apparently does so by interfering with the binding of ACh to its receptor. Comparative alignments with homologous sequences identified in other fish hunters revealed that αM-MIIIJ defines a new class of muscle nAChR inhibitors from cone snails.
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Figure 1. Sequence of αM-MIIIJ compared with those of other conotoxins. A. Sequence alignment of αM-MIIIJ with related sequences of unknown activity identified in C. magus, C. consors, and C. striatus (top) and M-superfamily conotoxins (bottom) that block V-gated Na channels (μ-prefix) or nAChRs (ψ-prefix for binding at a noncompetitive site). Cysteines are in bold. Identical amino acids are shown with arrowhead on top of αM-MIIIJ sequence. Z: pyroglutamic acid, O: hydroxyproline, #: C-terminal amidation. References [12,14,15,16,17,18,19,20]. B. Precursor sequence alignment of M-superfamily toxins highlights a conserved signal sequence used for toxin gene classification. The precursor sequence of αM-MIIIJ could not be retrieved, but high sequence similarities with αM-MIIIJ-like sequences, including MIIIK (91%), strongly suggest that αM-MIIIJ also belongs to the M-superfamily. Amino acid conservations are denoted by an asterisk (*). Full stops (.) and colons (:) represent a low and high degree of similarity, respectively. | |
Figure 2. αM-MIIIJ blocks excitatory synaptic responses but not action potentials in X. laevis longitudinal pectoralis (LP) muscle. Extracellular recording from adult muscle was performed as described in Methods. Graphs plot peak amplitudes of responses versus time, where presence of αM-MIIIJ is represented by black bar above each plot and insets show representative traces at the enumerated time points. Arrows in insets of panels A and C show when stimulus was applied. A and B. Muscle action potentials in response to indirect (A) and direct (B) stimulation. Ten μM αM-MIIIJ completely blocked action potentials evoked by nerve stimulation (A); in contrast, a five-times higher concentration of αM-MIIIJ had essentially no effect on action potentials evoked by direct stimulation (B). As a positive control, μ-PIIIA (10 μM), a conotoxin that irreversibly inhibits muscle V-gated Na channels, completely blocked action potentials within 10 min. (flat dashed trace of panel B’s inset). C. Motor-nerve stimulation evoked synaptic responses (without confounding muscle action potentials) in muscle preparation treated with μ-PIIIA (10 μM). The synaptic responses were reversibly blocked by 10 μM αM-MIIIJ. Each trace in inset of panel C represents the average of ~10 responses. Results replicating those illustrated here (i.e., complete block by toxin of nerve stimulation-evoked action potentials and synaptic responses, and conversely no block by toxin of direct stimulation-evoked action potentials) were obtained in three other LP muscle preparations. | |
Figure 3. Action and synaptic potentials in R. pipiens cutaneous pectoralis (CP) muscle are unaffected by αM-MIIIJ (100 μM). Muscle preparation and recording were as described in Methods. Format of presentation of results are as in Figure 2 (except traces in panel B were acquired with a low pass-filter setting of 0.1, instead of 1, Hz). Indirectly-evoked action potentials (A) and synaptic responses (B) are essentially unaffected by 100 μM αM-MIIIJ. In B, the muscle was treated with μ-PIIIA as in Figure 2C. As a positive control, the preparation was exposed to the muscle nAChR antagonist d-tubocurare (10 μM), which blocked within 15 min. (largely flat, dashed trace of panel B’s inset). These results indicate that αM-MIIIJ does not block the muscle action potential in R. pipiens (like in X. laevis) muscle, nor does αM-MIIIJ block (unlike in X. laevis) the synaptically-evoked response. Results replicating those illustrated here (i.e., no block of either action or synaptic potentials by toxin) were obtained in three other CP muscle preparations. | |
Figure 4. αM-MIIIJ blocks excitatory postsynaptic potentials (EPSPs), miniature excitatory postsynaptic potentials (MEPSPs), and ACh-evoked postsynaptic potentials (PSPs) in X. laevis LP muscle. Intracellular recording from juvenile muscle preparation was performed as described in Methods. All responses were obtained contemporaneously from one muscle fiber whose resting potential ranged between −77 to −88 mV. A–C. Time course of block by 0.2 or 10 μM αM-MIIIJ of EPSPs (A), MEPSPs (B), and ACh-evoked PSPs (C). The pair of asterisks along the top of panel B denotes the time interval flanked by the pair of asterisks in panel A. Insets in panels A and C show sample traces before (1) and in the presence of 0.2 μM αM-MIIIJ (2) or 10 μM αM-MIIIJ (3). Hump in falling phase of EPSPs in inset of panel A presumably reflects the multiple innervation of the fiber. Sample traces in panel B were obtained before (left) and in the presence of 0.2 μM αM-MIIIJ (right); each trace shows two MEPSPs, and the calibration scale applies to both traces. No MEPSPs were discernable in the presence of 10 µM αM-MIIIJ. Early spike of superimposed traces in inset of C is an artifact of the iontophoretic pulse. | |
Figure 5. αM-MIIIJ (10 μM) blocks MEPSPs in goldfish intercostal (IC) muscles. Intracellular recordings, performed as described in Methods, were obtained successively from six muscle fibers, A through F. Each data point represents the mean peak amplitude ± SD of at least 30 events. Recordings were made before (fibers A–C) and during (fibers C’–F) exposure to αM-MIIIJ (1 μM). After recordings from fiber C were acquired, the bath was supplemented with a high concentration of αM-MIIIJ such that its final concentration in the bath was 1 μM, and the recording recommenced (fiber C’) until the resting potential was abruptly lost. The resting potentials (in mV) of the respective fibers fibers were as follows: −67 (fiber A), −62 (fiber B), −92 (fiber C), −84 (fiber C’), −98 (fiber D), −65 (fiber E), and −101 (fiber F). In fibers D–F, no discernable MEPSPs were observed above the noise and indicated the block by 1 μM αM-MIIIJ was > 80% in each case. | |
Figure 6. Concentration-dependent block by αM-MIIIJ of synaptically- and ACh-evoked responses at frog and fish NMJs. Plot summarizing results with different concentrations of αM-MIIIJ from experiments of the sort illustrated in Figure 4; Figure 5. Percentage block of: EPSPs in X. laevis LP (circles, 2); spontaneous MEPSPs in X. laevis LP (squares, 4) and goldfish IC (diamond, which denotes the minimum block of 80% by 1 μM peptide in fibers D, E, and F in Figure 5); and ACh-evoked responses in X. laevis LP (triangles, 2). Each point represents one measurement. Block of EPSPs were not corrected for non-linear summation [24] and are therefore minimum estimates. Lines are curves of the Langmuir adsorption isotherm, % Block = 100%/{1 + (IC50/[Toxin])}, where [Toxin] is αM-MIIIJ concentration, and IC50 = 0.1, 0.05 or 0.2 μM (central bold-dotted line and flanking dashed lines, respectively). Experimental points lie close to or between the dashed lines and suggest an aggregate IC50 within a factor of about two of 0.1 μM. | |
Figure 7. αM-MIIIJ blocks ACh-gated currents (IACh) of voltage-clamped X. laevis oocytes exogenously expressing zebrafish nAChRs. Expression of nAChRs, induction of IACh in voltage-clamped oocytes, and toxin application and analysis of consequent effects were performed as described in Methods. Concentration-dependent block by αM-MIIIJ of three combinations of zebrafish nAChR subunits are plotted (αβδε, closed circles; αβδγ, open circles; and αβδ, open squares). Each data point represents mean ± SE (n = 3 or 4 oocytes). Solid line represents best-fit curve of the data to the Langmuir adsorption isotherm (see Table 2 for IC50s). Inset illustrates example IACh traces from an oocyte expressing the αβδ-subunit combination before (control), immediately after a 5-min. exposure to 330 nM αM-MIIJ, and following peptide washout at 1-min. intervals; duration of each trace is 4 sec. The block by αM-MIIIJ was readily reversible. | |
Figure 8. αM-MIIIA block of αβε nAChR (A), and washout kinetics from αβε AChR (B) and αβδε nAChR (C). These experiments were done essentially as in Figure 7. A. αM-MIIIJ concentration–response curve for block of αβε nAChR (see Table 2 for IC50). The data points follow a trajectory steeper than their fit to a Langmuir isotherm (solid curve), the significance of which remains to be determined. B, C. αM-MIIIJ washout curves from αβε (B) and αβδε (C) nAChRs. Solid line is the best-fit single-exponential curve with a koff of 0.80 min−1 (95% C.I. of 0.7–0.9) for αβε, and 0.76 min−1 (95% C.I. of 0.4–1.2) for αβδε. Data points represent mean ± S.E. (n = 3 for panels A and B; and n = 6 for panel C, from aggregate of open circles in Figure 9B,E below). | |
Figure 9. αM-MIIIJ (10 μM) protects zebrafish nAChRs against slowly-reversible block by α-EI and α-bungarotoxin (α-BgTX). ACh-gated currents from oocytes expressing zebrafish nAChRs were obtained as described in Methods. A given oocyte was first exposed to 10 μM αM-MIIIJ for 10 min. in a static bath, then perfused to observe the time course of recovery from block (open circles). The oocyte was then exposed again to 10 μM αM-MIIIJ for 5 min. in a static bath, after which the bath was supplemented with either 1 μM α-EI (open squares in panels A, B, and C) or 10 μg/mL α-BgTX (open squares in panels D, E, and F) and allowed to sit for another 5 min before the bath perfusion was recommenced. Finally, in a separate experiment, a given oocyte was exposed to either 1 μM α-EI alone (panels A, B, and C) or 10 μg/mL of α-BgTX alone (panels D, E, and F) for 5-min in a static bath before bath perfusion was recommenced (solid triangles). The time courses of recovery from block during the perfusion following the static-bath exposure to toxin(s) are plotted. Recovery from block following exposure to α-EI alone or α-BgTX alone was very slow in all panels (solid triangles). Furthermore, in all instances, except panel D, pre- and concurrent exposure to αM-MIIIJ prevented persistent block by α-EI and α-BgTX (as evident from similarity of time courses curves denoted by open circles and open squares). The divergent open-circle and open-square curves in panel D indicate that αM-MIIIJ only partially protected the αβδγ receptor against block by α-BgTX. α-BgTX use in these experiments was derivatized with tetramethylrhodamine (same stock solution as that used in fluorescence imaging experiments described below). | |
Figure 10. Block by α-conotoxin EI of zebrafish muscle nAChRs expressed in X. laevis oocytes. The block of IACh by conotoxin was assessed as described in Figure 7. Plotted are the concentration–response curves for the block by α-EI of αβδ (open squares), αβδγ (open circles), and αβδε (closed circles) nAChRs. Each data point represents mean ± S.E. (n = 3–5). (See Table 2 for IC50s.) Inset shows example IACh traces from an oocyte expressing αβδε nAChRs before and following a 5-min. exposure to 1 μM α-EI; duration of each trace is 5 s. The block by α-EI is only slowly reversible. | |
Figure 11. αM-MIIIJ (10 μM) blocks neuromuscular transmission in mouse muscle. Extracellular recording of the mouse levator auris longus (LAL) muscle’s action potential evoked by indirect stimulation was performed as described in Methods. Plot of peak (negative) amplitude of muscle action potential as a function of time before, during exposure to 10 μM αM-MIIIJ (indicated by black bar), and after toxin washout. Inset shows example traces of the extracellularly-recorded action potential before (trace 1), during block by toxin (trace 2) and after washout (trace 3), with trace numbers corresponding to times indicated in the main plot. The results are consistent with a low-potency block of mouse muscle nAChRs; direct evidence for this is illustrated in Figure 12. | |
Figure 12. αM-MIIIJ blocks mammalian muscle nAChRs with low potencies. Oocytes expressing nAChRs from human (A) and mouse (B) were voltage-clamped and exposed to αM-MIIIJ as described in Methods. Concentration–response curves for the block by αM-MIIIJ of IACh in oocytes expressing αβδγ (open circles) or αβδε (closed circles) subunits. Solid lines represent best-fit curves to the Langmuir isotherm (see Table 2 for IC50s). | |
Figure 13. αM-MIIIJ (10 μM) inhibits binding of TMR α-BgTX at neuromuscular junctions of X. laevis LP muscle. Preparation of muscles, image acquisition, and quantification of fluorescence were performed as described in Methods. A. Two preparations, Muscle I and Muscle II, were stained with f-PNA so locations of NMJs could be identified as described in Methods. In Muscle I, the NFR bathing the muscle was replaced (at t = 10′) with 1 μg/mL TMR α-BgTX, and the NMJ was periodically imaged while its staining ensued until a steady state was achieved (squares). Muscle II was treated with 10 μM αM-MIIIJ (at t = 0) for 10-min. before it was exposed to 1 μg/mL TMR α-BgTX + 10 μM αM-MIIIJ, after which the endplate was periodically imaged for 30-min. (gray circles). Then the solution bathing muscle II was removed and reserved, and the muscle rinsed. After ~90-min., Muscle II was exposed to 1 μg/mL TMR α-BgTX alone while the NMJ was periodically imaged until the fluorescence reached steady state (black circles). The steady-state level of fluorescence varied from one NMJ to the next, so the fluorescence values at each endplate were normalized to the value obtained at steady state (at t ≈ 30′ for Muscle I and t ≈ 140′ for Muscle II). Each data point represents the mean ± SD from 9 to 12 regions of interest (ROIs; see rectangle in panel C) obtained along the NMJ. Presence of αM-MIIIJ clearly interfered with α-BgTX binding. B and E. f-PNA staining of an NMJ from X. laevis LP muscle (B) and R. pipiens CP muscle (E). C and F. TMR α-BgTX staining of X. laevis LP muscle (C) and R. pipiens CP muscle (F). Here, the CP muscle was treated with the reserved TMR α-BgTX + αM-MIIIJ solution removed from Muscle II; nevertheless, strong TMR staining is clearly evident. D and G. Overlays of images in panels B and C (D) and panels E and F (G). H. Fluorescence profile from the ROI in panel C (see rectangle therein). Calibration bar (20 μm, white line) in G applies to panels B through G. Presence of αM-MIIIJ clearly inhibited the binding of TMR α-BgTX at the NMJ of the X. laevis LP muscle but not at that of the R. pipiens CP muscle. |
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