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ZOO4670/5670 Lecture No. 6 Neurotoxins as Tools for Studying Ion Channel Structure and Functions Qian-Quan Sun Ph.D ([email protected]) Univ. Wyoming Today’s outline • 1. Basics about channel block • 2. Snake toxins and potassium channels • 3. Sodium channels: toxins and local anesthetics • 4. Sea snails, spiders and calcium channels 1 Apamin Honey bee Blocks Ca2+ activated potassium channels Honey bee Stichodactyla Toxin Sea Anemone Blocks voltage-gated potassium channels sea anemone 2 3 Palytoxin Soft coral Activates sodium channels Capsaicin Cayenne Pepper Excites peripheral nerve endings 4 Poison Arrow Batrachotoxin Prevents sodium channels from closing Frog Blue-Ringed Maculotoxin Blocks sodium channels Octopus 5 Model or State 1 State 2 all molecules scheme begin here at t= 0 k21 normal function closed open units: s-1 units: M-1s-1 + k23 = k [Drug] k 21 drug simple block closed open blocked current time constant time constant = 1/k21 = 1/(k21+ k23) none Ligand binding and dose response curve Concentration of toxin (nM) 6 use-dependent block= open channel blocker inside “Trapped” or Functioning channel “Use-Dependent” Blocker Antiarrhythmics (heart) Antiepileptics / anticonvulsants (brain) “use-dependent blocker” “use-dependent blocker” example: (procainamide) (phenytoin = Dilantin® ) A use-dependent blocker stimuli impulses fail impulses (voltage) channel population threshold (currents) pronounced block little block at brief intervals at long intervals 7 Green mamba snake Pore region sequence of ShaKv1.1. The dendrotoxin receptor surface of ShaKv1.1. KcsA The surface color represents the change in binding energy of dendrotoxin associated with mutation 8 Conclusions: dendrotoxin binds near the pore entryway but does not act as a physical plug. Hypothetical binding orientation for dendrotoxin Scorpion toxin fits even better to the pore entryway! Binding orientation of scorpion toxin on the K. channel. 9 C11H17N3O8 Tetrodotoxin alpha-scorpion toxin beta-scorpion toxins Sea anemone Motif III b-scorpion toxins trap Kd =0.1nM IIS4 in the outward, activated position. Channel must be activated for toxin effect. a-scorpion toxin trap IVS4 in an inward, partially activated position. Motif I Prolonged depolarization drives the toxins off their Motif IV receptor site 10 Neurotoxins that block Na+ channels Local Anesthetics Antiarrhythmic Etidocaine Drugs Lidocaine Lidocaine Mexiletine Many others Quinidine Flecainide Anticonvulsants Phenytoin Carbamazepine Lamotrigine use dependent block 11 Baldomero “Toto” Olivera Ph D [email protected] Distinguished Professor Olivera lab directory Geographer’s cone Magician’s cone Leopard cone Cloth-of-gold cone 12 A conotoxin: 27 amino acids held together by disulfide bonds individual conotoxins specifically block individual ion channels. 13 The lethal sea snail toxin is a promising pain killer . Ziconotide is the synthetic equivalent of a 25-amino-acid, polybasic peptide from the venom of Conus magus, a marine snail. It is the first selective N-type, voltage-sensitive calcium-channel blocking agent to reach clinical trials. In the current study, patients aged 24 to 85 years with refractory pain from advanced cancer or AIDS were randomized to ziconotide or placebo in a 2:1 ratio. Intrathecal ziconotide was titrated over 5 to 6 days, followed by a 5-day maintenance phase. Mean pain scores improved 52.9% in the ziconotide group, compared with 17.5% in the placebo group, with no reduction in efficacy during the maintenance phase. Five patients receiving ziconotide achieved complete pain relief. Ziconotide also seems to improve the sleep pattern in some patients with chronic severe pain. Patients experienced positive effects on nocturnal sleep duration and believed that remaining pain symptoms interfered less with their daily life. In experimental studies of absorption, distribution, metabolism, and elimination, intrathecal ziconotide appeared and diminished rapidly in plasma and resulted in relatively little plasma protein binding. Intravenous ziconotide degraded in animal brain tissue in 2 to 24 hours, produced no detectable intermediates, and was cleared quickly from both cerebrospinal fluid (CSF) and the circulatory system. This accelerated clearance rate likely means that the distribution of ziconotide throughout CSF and metabolism within CSF are also rapid. 14 Cerebral cortex (layer II/III) Thalamus Trigeminal nucleus 15 Voodoo • Ancient haitian traditions used the puffer fish for its voodoo practices. – The tetrodotoxin is used to create zombies – It puts the people in a death-like state • The towns people would take some to be put into this state – While under this state, they would be forced to do odd jobs. - The zombies were used as a social damper to scare towns people to keep them in line. Toxins that act on voltage-gated ion channels Name Source Neuronal Action Funnel Web Agatoxin Blocks calcium channels Spider Agitoxin Scorpion Blocks potassium channels Apamin Honey bee Blocks potassium channels Blue Mountains Atracotoxin Funnel Web Blocks voltage-gated calcium channels Spider Poison Arrow Batrachotoxin Prevents sodium channels from closing Frog Capsaicin Cayenne Pepper Excites peripheral nerve endings Charybdotoxin Scorpion Blocks potassium channels Ciguatoxin Dinoflagellate Opens sodium channels Conotoxin Marine Snail voltage-sensitive calcium channels; sodium channels Dendrotoxin Green Mamba Blocks voltage-gated potassium channels South American Grammotoxin Rose Blocks calcium channels SIA Tarantula Gonyautoxin Dinoflagellate Blocks sodium channels Iberiotoxin Scorpion Blocks potassium channels Kaliotoxin Scorpion Blocks potassium channels South African Kurtoxin Blocks calcium channels Scorpion 16 Toxins that act on voltage-gated ion channels: continued Blue-Ringed Maculotoxin Blocks sodium channels Octopus Margatoxin Scorpion Blocks potassium channels Noxiustoxin Scorpion Blocks sodium channels Palytoxin Soft coral Activates sodium channels Phoneutriatoxin Banana spider Slows sodium channel inactivation Chilean fire Phrixotoxin Blocks potassium channels tarantula Funnel web Robustotoxin Opens sodium channels spider Saxitoxin Dinoflagellate Blocks sodium channels SNX-482 African Tarantula Blocks calcium channels Stichodactyla Blocks voltage-gated potassium Sea Anemone Toxin channels Australian Taipan Taicatoxin Inhibits voltage-gated calcium channels snake Tetrodotoxin Pufferfish Blocks sodium channels (TTX) Brazilian Tityustoxin-K Blocks potassium channels Scorpion Funnel web Versutoxin Opens sodium channels spider 17.
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