Calcicludine

Last updated

Calcicludine (CaC) is a protein toxin from the venom of the green mamba that inhibits high-voltage-activated calcium channels, especially L-type calcium channels.

Contents

Sources

Calcicludine is a toxin in the venom of the green mamba (Dendroaspis angusticeps).

Chemistry

Calcicludine is a 60-amino acid polypeptide with six cysteines forming three disulfide bridges. Calcicludine structurally resembles dendrotoxin, but works differently, since even at high concentrations, calcicludine has no effect on dendrotoxin-sensitive potassium channels in chicken and rat neurons. [1]

Target

Calcicludine is a blocker of high-voltage-activated calcium channels (L-, N- and P-type channels). It has highest affinity to the L-type calcium channel (IC50 = 88nM[2]). However, sensitivity of the drug on the channel depends on the species and the tissue. For example, the IC50 for block of L-type calcium channels on a cerebellar granule cell is 0.2 nM, but the IC50 of the block of rat peripheral DRG neuronal L-type channels is around 60-80 nM. [1]

Mode of Action

Calcicludine has a unique mode of action, which is still incompletely understood. It has been suggested to act by a partial pore block or an effect on channel gating. [2]

Toxicity

Calcicludine has been shown to work on rat cardiac cells and rat cerebellum granule cells. [1]

Related Research Articles

<span class="mw-page-title-main">Dendrotoxin</span> Chemical compound

Dendrotoxins are a class of presynaptic neurotoxins produced by mamba snakes (Dendroaspis) that block particular subtypes of voltage-gated potassium channels in neurons, thereby enhancing the release of acetylcholine at neuromuscular junctions. Because of their high potency and selectivity for potassium channels, dendrotoxins have proven to be extremely useful as pharmacological tools for studying the structure and function of these ion channel proteins.

<span class="mw-page-title-main">Eastern green mamba</span> Species of venomous snake

The eastern green mamba is a highly venomous snake species of the mamba genus Dendroaspis native to the coastal regions of southern East Africa. Described by Scottish surgeon and zoologist Andrew Smith in 1849, it has a slender build with a bright green back and green-yellow ventral scales. Adult females average around 2 metres in length, and males are slightly smaller.

omega-Grammotoxin SIA (ω-grammotoxin SIA) is a protein toxin that inhibits P, Q, and N voltage-gated calcium channels (Ca2+ channels) in neurons.

Taicatoxin (TCX) is a snake toxin that blocks voltage-dependent L-type calcium channels and small conductance Ca2+-activated K+ channels. The name taicatoxin (TAIpan + CAlcium + TOXIN) is derived from its natural source, the taipan snake, the site of its action, calcium channels, and from its function as a toxin. Taicatoxin was isolated from the venom of Australian taipan snake, Oxyuranus scutellatus scutellatus. TCX is a secreted protein, produced in the venom gland of the snake.

Kurtoxin is a toxin found in the venom of the scorpion Parabuthus transvaalicus. It affects the gating of voltage-gated sodium channels and calcium channels.

<span class="mw-page-title-main">Calciseptine</span> Neurotoxin

Calciseptine (CaS) is a natural neurotoxin isolated from the black mamba Dendroaspis p. polylepis venom. This toxin consists of 60 amino acids with four disulfide bonds. Calciseptine specifically blocks L-type calcium channels, but not other voltage-dependent Ca2+ channels such as N-type and T-type channels.

<span class="mw-page-title-main">Margatoxin</span>

Margatoxin (MgTX) is a peptide that selectively inhibits Kv1.3 voltage-dependent potassium channels. It is found in the venom of Centruroides margaritatus, also known as the Central American Bark Scorpion. Margatoxin was first discovered in 1993. It was purified from scorpion venom and its amino acid sequence was determined.

<span class="mw-page-title-main">Grammotoxin</span>

Grammotoxin is a toxin in the venom of the tarantula Grammostola spatulata. It is a protein toxin that inhibits P-, Q- and N-type voltage-gated calcium channels in neurons. Grammotoxin is also known as omega-grammotoxin SIA.

The P-type calcium channel is a type of voltage-dependent calcium channel. Similar to many other high-voltage-gated calcium channels, the α1 subunit determines most of the channel's properties. The 'P' signifies cerebellar Purkinje cells, referring to the channel's initial site of discovery. P-type calcium channels play a similar role to the N-type calcium channel in neurotransmitter release at the presynaptic terminal and in neuronal integration in many neuronal types.

<span class="mw-page-title-main">Agatoxin</span>

Agatoxins are a class of chemically diverse polyamine and peptide toxins which are isolated from the venom of various spiders. Their mechanism of action includes blockade of glutamate-gated ion channels, voltage-gated sodium channels, or voltage-dependent calcium channels. Agatoxin is named after the funnel web spider which produces a venom containing several agatoxins. There are different agatoxins. The ω‎-agatoxins are approximately 100 amino acids in length and are antagonists of voltage-sensitive calcium channels and also block the release of neurotransmitters. For instance, the ω‎-agatoxin 1A is a selective blocker and will block L-type calcium channels whereas the ω‎-agatoxin 4B will inhibit voltage sensitive P-type calcium channels. The μ‎-agatoxins only act on insect voltage-gated sodium channels.

Stromatoxin is a spider toxin that blocks certain delayed-rectifier and A-type voltage-gated potassium channels.

<span class="mw-page-title-main">Tertiapin</span>

Tertiapin is a 21-amino acid peptide isolated from venom of the European honey bee. It blocks two different types of potassium channels, inward rectifier potassium channels (Kir) and calcium activated large conductance potassium channels (BK).

Discrepin (α-KTx15.6) is a peptide from the venom of the Venezuelan scorpion Tityus discrepans. It acts as a neurotoxin by irreversibly blocking A-type voltage-dependent K+-channels.

<span class="mw-page-title-main">Acid-sensing ion channel</span> Class of transport proteins

Acid-sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels activated by extracellular protons permeable to Na+. ASIC1 also shows low Ca2+ permeability. ASIC proteins are a subfamily of the ENaC/Deg superfamily of ion channels. These genes have splice variants that encode for several isoforms that are marked by a suffix. In mammals, acid-sensing ion channels (ASIC) are encoded by five genes that produce ASIC protein subunits: ASIC1, ASIC2, ASIC3, ASIC4, and ASIC5. Three of these protein subunits assemble to form the ASIC, which can combine into both homotrimeric and heterotrimeric channels typically found in both the central nervous system and peripheral nervous system. However, the most common ASICs are ASIC1a and ASIC1a/2a and ASIC3. ASIC2b is non-functional on its own but modulates channel activity when participating in heteromultimers and ASIC4 has no known function. On a broad scale, ASICs are potential drug targets due to their involvement in pathological states such as retinal damage, seizures, and ischemic brain injury.

Helothermine is a toxin from the venom of the Mexican beaded lizard Heloderma horridum horridum. Helothermine inhibits ryanodine receptors, calcium channels and potassium channels. Helothermine can cause lethargy, partial paralysis of rear limbs and lowering of the body temperature.

Huwentoxins (HWTX) are a group of neurotoxic peptides found in the venom of the Chinese bird spider Haplopelma schmidti. The species was formerly known as Haplopelma huwenum, Ornithoctonus huwena and Selenocosmia huwena. While structural similarity can be found among several of these toxins, HWTX as a group possess high functional diversity.

AmmTX3, produced by Androctonus mauretanicus, is a scorpion toxin of the α-KTX15 subfamily. The toxin is known for its ability to act as a specific Kv4 channel blocker, and thereby reducing the A-type potassium current through this channel.

HsTx1 is a toxin from the venom of the scorpion Heterometrus spinifer. HsTx1 is a very potent inhibitor of the rat Kv1.3 voltage-gated potassium channel.

Protoxin-II, also known as ProTx-II, PT-II or β/ω-TRTX-Tp2a, is a neurotoxin that inhibits certain voltage-gated calcium and voltage-gated sodium channels. This toxin is a 30-residue disulfide-rich peptide that has unusually high affinity and selectivity toward the human Nav1.7. channel.

AsKC11 is a toxin found in the venom of the sea anemone, Anemonia sulcata. This toxin is part of the Kunitz peptide family and has been shown to be an activator of G protein-coupled inwardly-rectifying potassium (GIRK) channels 1/2, involved in the regulation of cellular excitability. 

References

  1. 1 2 3 Schweitz H, Heurteaux C, Bois P, Moinier D, Romey G, Lazdunski M (February 1994). "Calcicludine, a venom peptide of the Kunitz-type protease inhibitor family, is a potent blocker of high-threshold Ca2+ channels with a high affinity for L-type channels in cerebellar granule neurons". Proc Natl Acad Sci USA. 91 (3): 878–82. Bibcode:1994PNAS...91..878S. doi: 10.1073/pnas.91.3.878 . PMC   521415 . PMID   8302860.
  2. Stotz SC, Spaetgens RL, Zamponi GW (March 2000). "Block of voltage-dependent calcium channel by the green mamba toxin calcicludine". J. Membr. Biol. 174 (2): 157–65. doi:10.1007/s002320001040. PMID   10742459. S2CID   20776129. Archived from the original on 2000-09-15. Retrieved 2009-02-06.