The rates of saxitoxin action and of saxitoxin-tetrodotoxin interaction at the node of Ranvier

Wagner, H.-H.; Ulbricht, W.

doi:10.1007/bf00581441

Cited by 52 publications

(11 citation statements)

References 29 publications

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“…We find almost identical values (at -120 mV) of 2 x 107 M-1 sec'1 for both QX-222 and QX-314, which is within one order of magnitude of the binding rate for some barbiturates and almost identical to the binding rate of procaine (Adams, 1976(Adams, , 1977. As pointed out before by Adams (1976) this value is also similar to blocking rates found for STX (1.01 x 107) and TTX in frog node Na+-channels (Wagner & Ulbricht, 1975). Also, it is close to the rate of TEA blocking of squid K+-channel (Armstrong, 1966) and to the rate of block of squid Na+-channels by pancuronium (Yeh & Narahashi, 1977).…”

Section: Discussionsupporting

confidence: 87%

Local anaesthetics transiently block currents through single acetylcholine‐receptor channels.

Neher¹,

Steinbach²

1978

The Journal of Physiology

804

657

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SUMMARY1. Single channel currents through acetylcholine receptor channels (ACh channels) were recorded at chronically denervated frog muscle extrajunctional membranes in the absence and presence of the lidocaine derivatives QX-222 and QX-314.2. The current wave forms due to the opening and closing of single ACh channels (activated by suberyldicholine) normally are square pulses. These single pulses appear to be chopped into bursts of much shorter pulses, when the drug QX-222 is present in addition to the agonist.3. The mean duration of the bursts is comparable to or longer than the normal channel open time, and increases with increasing drug concentration.4. The duration of the short pulses within a burst decreases with increasing drug concentration.5. It is concluded that drug molecules reversibly block open end-plate channels and that the flickering within a burst represents this fast, repeatedly occurring reaction.6. The voltage dependence of the reaction rates involved, suggested that the site of the blocking reaction is in the centre of the membrane, probably inside the ionic channel.

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Section: Discussionsupporting

confidence: 87%

Local anaesthetics transiently block currents through single acetylcholine‐receptor channels.

Neher¹,

Steinbach²

1978

The Journal of Physiology

804

657

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“…The observed EDs0 of 4.9 nM shows that at pH 6.50 STX is slightly less potent than at pH 7.25. Although the difference between the observed EDs0's at pH's 6.50 and 7.25 is not statistically significant (P > 0.3), a similar observation has been made by a number of investigators before (e.g., Wagner and Ulbricht, 1975;Barchi and Weigel, 1979;Strichartz, 1984). Such a discrepancy also occurs for both neoSTX and TI'X.…”

Section: Stxsupporting

confidence: 79%

Interactions of neosaxitoxin with the sodium channel of the frog skeletal muscle fiber.

Kao

1991

The Journal of General Physiology

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Neosaxitoxin (neoSTX) differs structurally from saxitoxin (STX) in that the hydrogen on N-1 is replaced by a hydroxyl group. On single frog skeletal muscle fibers in the vaseline-gap voltage clamp, the concentrations for reducing the maximum sodium current by 50% (EDs0) at pH's 6.50, 7.25, and 8.25 are, respectively, 4.9, 5.1, and 8.9 nM for STX and 1.6, 2.7, and 17.2 nM for neoSTX. The relative potencies of STX at the different pH's closely parallel the relative abundance of the protonated form of the 7,8,9 guanidinium function, but the relative potencies of neoSTX at the same pH's vary with the relative abundance of the deprotonated N-1 group. In constant-ratio mixtures of the two toxins, the observed EDs0's are consistent with the notion that the two toxins compete for the same site. At pH's 6.50 and 7.25, the best agreement between observed and computed values is obtained when the efficacy term (c) for either toxin is 1. At pH 8.25 the best agreement is obtained if the efficacy is 1 for STX but 0.75 for neo-STX. The marked pH dependence of the actions of neoSTX probably reflects the presence of a site in the receptor that interacts with the N-1 -OH, in addition to those interacting with the 7,8,9 guanidinium and the C-12 hydroxyl groups. Considering the three-dimensional structure of the STX and neoSTX molecules, the various site points are probably located in a fold or a crevice of the channel protein, where the extracellular orifice of the sodium channel is located.

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“…In this study, the forward blocking rate constant for 9-AA binding has been estimated to be on the order of 1 x 10 7 M-'s -' . This value is within the same order of magnitude as that for QX-222, QX-314 (Neher and Steinbach, 1978), barbiturates, procaine (Adams, 1976(Adams, , 1977, and octylguanidine (Farley et al ., 1981) in blocking ACh-activated channels from the outside, and that for Sax]toxin, tetrodotoxin (Wagner and Ulbricht, 1975), and pancuronium (Yeh and Narahashi, 1977) in blocking Na channels, and that for TEA in blocking K channels in nerve membranes from the inside (Armstrong, 1966). The similar rate of block by such a large class of different substances suggests that the binding reaction is probably diffusion controlled .…”

Section: -Aa Caused Flickering In the Single Na Channelmentioning

confidence: 95%

Kinetics of 9-aminoacridine block of single Na channels.

Yamamoto¹,

Yeh²

1984

The Journal of General Physiology

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The kinetics of 9-aminoacridine (9-AA) block of single Na channels in neuroblastoma N 1 E-115 cells were studied using the gigohm seal, patch clamp technique, under the condition in which the Na current inactivation had been eliminated by treatment with N-bromoacetamide (NBA) . Following NBA treatment, the current flowing through individual Na channels was manifested by square-wave open events lasting from several to tens of milliseconds . When 9-AA was applied to the cytoplasmic face of Na channels at concentrations ranging from 30 to 100 /M, it caused repetitive rapid transitions (flickering) between open and blocked states within single openings of Na channels, without affecting the amplitude of the single channel current . The histograms for the duration of blocked states and the histograms for the duration of open states could be fitted with a single-exponential function . The mean open time (To) became shorter as the drug concentration was increased, while the mean blocked time (Tb) was concentration independent . The association (blocking) rate constant, k, calculated from the slope of the curve relating the reciprocal mean open time to 9-AA concentration, showed little voltage dependence, the rate constant being on the order of 1 x 10' M's' . The dissociation (unblocking) rate constant, l, calculated from the mean blocked time, was strongly voltage dependent, the mean rate constant being 214 s' at 0 mV and becoming larger as the membrane being hyperpolarized . The voltage dependence suggests that a first-order blocking site is located at least 63% of the way through the membrane field from the cytoplasmic surface . The equilibrium dissociation constant for 9-AA to block the Na channel, defined by the relation of 11k, was calculated to be 21 uM at 0 mV. Both To' and Tb' had a Q10 of 1 .3, which suggests that binding reaction was diffusion controlled . The burst time in the presence of 9-AA, which is the sum ofopen times and blocked times, was longer than the lifetime of open channels in the absence of drug. All of the features of 9-AA block of single Na channels are compatible with the sequential model in which 9-AA molecules block open Na channels, and the blocked channels could not close until 9-AA molecules had left the blocking site in the channels .

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The rates of saxitoxin action and of saxitoxin-tetrodotoxin interaction at the node of Ranvier

Cited by 52 publications

References 29 publications

Local anaesthetics transiently block currents through single acetylcholine‐receptor channels.

Local anaesthetics transiently block currents through single acetylcholine‐receptor channels.

Interactions of neosaxitoxin with the sodium channel of the frog skeletal muscle fiber.

Kinetics of 9-aminoacridine block of single Na channels.

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