Atrotoxin: A Specific Agonist for Calcium Currents in Heart

Hamilton, Susan L.; Yatani, Atsuko; Hawkes, Mary Jane; Redding, Kevin; Brown, Arthur M.

doi:10.1126/science.3160111

Cited by 40 publications

(6 citation statements)

References 23 publications

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“…Snake venom neurotoxins, represented by α‐neurotoxins and dendrotoxins, are thought to be found mostly in Elapidae snake venoms [21,31], and only a few snake venom neurotoxins have been isolated from Viperidae snakes [32–36]. Recently, Brown et al .…”

Section: Discussionmentioning

confidence: 99%

“…Snake venom neurotoxins, represented by a-neurotoxins and dendrotoxins, are thought to be found mostly in Elapidae snake venoms [21,31], and only a few snake venom neurotoxins have been isolated from Viperidae snakes [32][33][34][35][36]. Recently, Brown et al isolated a 24-kDa cyclic nucleotide-gated ion channel blocker (designated pseudechetoxin; PsTx) from the venom of the Australian King Brown snake (Pseudechis australis, Elapidae) [50].…”

Section: Discussionmentioning

confidence: 99%

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Cloning and characterization of novel snake venom proteins that block smooth muscle contraction

Yamazaki¹,

Koike²,

Sugiyama³

et al. 2002

European Journal of Biochemistry

139

104

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In this study, we isolated a 25-kDa novel snake venom protein, designated ablomin, from the venom of the Japanese Mamushi snake (Agkistrodon blomhoffi). The amino-acid sequence of this protein was determined by peptide sequencing and cDNA cloning. The deduced sequence showed high similarity to helothermine from the Mexican beaded lizard (Heloderma horridum horridum), which blocks voltage-gated calcium and potassium channels, and ryanodine receptors. Ablomin blocked contraction of rat tail arterial smooth muscle elicited by high K + -induced depolarization in the 0.1-1 lM range, but did not block caffeine-stimulated contraction. Furthermore, we isolated three other proteins from snake venoms that are homologous to ablomin and cloned the corresponding cDNAs. Two of these homologous proteins, triflin and latisemin, also inhibited high K + -induced contraction of the artery. These results indicate that several snake venoms contain novel proteins with neurotoxin-like activity.Keywords: snake venom; neurotoxin; helothermine; cysteinerich secretory proteins; ablomin.Over the past 30 years, a plethora of toxins have been isolated from poisonous organisms, such as snakes, scorpions, spiders, and micro-organisms. These natural toxins use a variety of approaches to arrest the homeostatic mechanisms of other living organisms, including disruption of intracellular signal transduction and cytoskeleton organization [1][2][3][4], and activation or inhibition of blood coagulation factors [5][6][7][8][9][10]. Toxins that block synaptic transmission, called neurotoxins, are widely distributed in venoms. These toxins include the conotoxins from cone snails, agatoxins from spiders, and scorpion toxins [11][12][13][14][15][16]. These toxins exert their potentially lethal effects by specifically and potently blocking a variety of ion channels, including those that conduct Na + , K + , and Ca 2+ . Therefore, neurotoxins have been employed as useful tools to investigate the structure and function of these ion channels [17][18][19][20]. A large number of neurotoxin families have also been found in the venom of Elapidae snakes. These toxins, the a-neurotoxins [21] (represented by a-bungarotoxin [22,23], a-cobratoxin [24][25][26][27], and erabutoxin [28,29]) potently and specifically prevent nicotinic acetylcholine receptor activation. A second family of snake venom neurotoxins, the dendrotoxins, are homologous to Kunitz-type serine protease inhibitors and act primarily by blocking neuronal K + channels [30,31]. In contrast to the neurotoxin-rich venom from Elapidae snakes, the venom from other deadly snakes, including Viperidae and Colubridae snakes, contain surprisingly few neurotoxins, although some neurotoxic phospholipases have been discovered [32][33][34][35][36].In this report, we describe the isolation of a novel protein, ablomin, from the venom of the Japanese Mamushi snake (Agkistrodon blomhoffi, a member of the Viperidae family). When applied to arterial smooth muscle preparations from rat-tails, ablomin blocks K + -stimulated c...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cloning and characterization of novel snake venom proteins that block smooth muscle contraction

Yamazaki¹,

Koike²,

Sugiyama³

et al. 2002

European Journal of Biochemistry

139

104

View full text Add to dashboard Cite

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“…The complicated effects of the DHPs also presage difficulties in using them as labels for the biochemical isolation of Ca channels. Larger membrane-impermeable toxin molecules may be better candidates (Hamilton, Yatani, Hawkes, Redding & Brown, 1985).…”

Section: Discussionmentioning

confidence: 99%

Dual effects of dihydropyridines on whole cell and unitary calcium currents in single ventricular cells of guinea‐pig.

Brown

Kunze

Yatani

1986

The Journal of Physiology

131

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SUMMARY1. We studied the effects of dihydropyridine Ca channel ligands (DHPs), mainly nitrendipine and Bay K8644, on whole cell and single channel Ca currents on single myocytes isolated from the adult guinea-pig ventricle.2. Nitrendipine had dual effects, stimulatory or inhibitory, depending upon the membrane potential. At low frequencies (less than 0 03 Hz) and negative holding potentials (-90 mV or more), nitrendipine increased the Ca currents in a dosedependent manner. The dose-response curve was best fitted by a Langmuir adsorption isotherm model which was the sum of two independent one-to-one drug-receptor sites with median effective doses (ED50s) of 1.0 x 10-9 M and 1-4 x 10-6 M respectively.3. When the membrane potential was held at -30 mV or less, nitrendipine inhibited the Ca currents, also in a dose-dependent manner. The dose-response curve was fitted by a single binding site model having a median inhibitor concentration (IC50) of 15 x 10-9 M. At holding potentials between -70 and -40 mV, nitrendipine produced mixed effects on Ca currents; an increase occurred initially and this was followed by a decrease.4. When rundown was excluded, Bay K8644 showed only stimulatory effects on the Ca currents between holding potentials of -120 and -30 mV. When the test potential was zero or + 10 mV the Ca currents reached peak values and the dose-response curve was best fitted by a single binding site model having an ED50 of 3 x 1o-8 M. When the effects were measured at negative test potentials of -30 to -10 mV, the curve was best fitted by a two-site model with ED50s of 3 x 10-9 and 9x 10-7M.5. At the single Ca channel level the stimulatory effect of nitrendipine was due to an increased probability that a Ca channel which had opened once would reopen, a reduction in records without activity and an increase in the mean open time. There were no changes in unit conductance. Inhibitory effects were due to a large increase in nulls. At lower concentrations the main effect of Bay K8644 was an increase in * Present address, to which reprint requests should be sent:

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“…Various synthetic drugs and naturally occumng toxins enhance Ca2+ flux through voltage-dependent channels (Miller, 1984;Hamilton et al, 1985;Preuss et al, 1985). 'The best characterized of these agents is the dihydropyndine Ca2+ channel agonist BAY K 8644, which stimulates 45Ca2+ uptake and competes for Ca2+ channel 3H-labeled antagonist binding sites in PC12 cells (Greenberg et al, 1984(Greenberg et al, , 1985a.…”

Section: Discussionmentioning

confidence: 99%

Lectin‐Induced Enhancement of Voltage‐Dependent Calcium Flux and Calcium Channel Antagonist Binding

Greenberg

Carpenter

Messing

1987

Journal of Neurochemistry

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Concanavalin A (Con A), a tetravalent lectin with preferential affinity for mannosyl and glucosyl residues of membrane glycoconjugates, increased K+ depolarization-evoked uptake of 45Ca2+ in the PC12 neural cell line. Enhancement of uptake by Con A was concentration dependent, with maximal (24%) stimulation at 100 micrograms/ml of Con A, and was preferentially inhibited by mannoside and glucoside. Succinyl-Con A, a divalent analog with reduced biological potency, increased uptake by only 7%. The effect of Con A on 45Ca2+ uptake was dependent on membrane depolarization, was abolished by ionic Ca2+ channel blockers and organic Ca2+ channel antagonists, and was accompanied by an equivalent increase in Ca2+ channel 3H-labeled antagonist binding, observations suggesting that the voltage-dependent Ca2+ channel was the site of Ca2+ entry. The mechanism for enhancement of 45Ca2+ uptake by Con A appeared to be separate from that used by the Ca2+ channel agonist BAY K 8644 and independent of that involved in Ca2+ channel regulation by phorbol esters. These findings suggest that voltage-dependent Ca2+ channels may link cell surface carbohydrate interactions with intracellular effector processes.

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Atrotoxin: A Specific Agonist for Calcium Currents in Heart

Cited by 40 publications

References 23 publications

Cloning and characterization of novel snake venom proteins that block smooth muscle contraction

Cloning and characterization of novel snake venom proteins that block smooth muscle contraction

Dual effects of dihydropyridines on whole cell and unitary calcium currents in single ventricular cells of guinea‐pig.

Lectin‐Induced Enhancement of Voltage‐Dependent Calcium Flux and Calcium Channel Antagonist Binding

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