Jingzhaotoxin

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s are part of a

venom Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a sti ...

secreted by '' Chilobrachys jingzhao'', the Chinese

tarantula Tarantulas comprise a group of large and often hairy spiders of the family Theraphosidae. , 1,040 species have been identified, with 156 genera. The term "tarantula" is usually used to describe members of the family Theraphosidae, although ...

. and act as

neurotoxins Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and mature nerv ...

. There are several subtypes of jingzhaotoxin, which differ in terms of channel selectivity and modification characteristics. All subspecies act as gating modifiers of

sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...

s and/or, to a lesser extent,

potassium channel Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...

Sources

''Chilobrachys jingzhao'', also known as the Chinese earth tiger

or ''Chilobrachys guangxiensis'', can be found in China and Asia. This large tarantula belongs to the family of

Theraphosidae Tarantulas comprise a group of large and often hairy spiders of the family Theraphosidae. , 1,040 species have been identified, with 156 genera. The term "tarantula" is usually used to describe members of the family Theraphosidae, although m ...

Taxonomy Taxonomy is the practice and science of categorization or classification. A taxonomy (or taxonomical classification) is a scheme of classification, especially a hierarchical classification, in which things are organized into groups or types. ...

Chilobrachys Jingzhao

Chemistry

Jingzhaotoxins reported on this page are 29-36-residue polypeptides with varying numbers of stabilizing disulfide bridges.Liao, Z., Cao, J., Li, S., Yan, X., Hu, W., He, Q., Chen, J., Tang, J., Xie, J., & Liang, S. (2007). Proteomic and peptidomic analysis of the venom from Chinese tarantula Chilobrachys jingzhao. ''Proteomics, 7'', 1892-1907.Chen, J., Zhang, Y., Rong, M., Zhao, L., Jiang, L., Zhang, D., Wang, M., Xiao, Y., & Liang, S. (2009). Expression and characterization of jingzhaotoxin-34, a novel neurotoxin from the venom of the tarantula Chilobrachys jingzhao. ''Peptides, 30'', 1042-1048.Deng, M., Kuang, F., Sun, Z., Tao, H., Cai, T., Zhong, L., Chen, Z., Xiao, Y., & Liang, S. (2009). Jingzhaotoxin-IX, a novel gating modifier of both sodium and potassium channels from Chinese tarantula Chilobrachys jingzhao. ''Neuropharmacology, 57'', 77-87.Liao, Z., Yuan, C., Deng, M., Li, J., Chen, J., Yang, Y., Hu, W., & Liang, S. (2006). Solution Structure and Functional Characterization of Jingzhaotoxin-XI: A Novel Gating Modifier of both Potassium and Sodium Channels. ''Biochemistry, 45'', 15591-15600Liao, Z., Yuan, C., Peng, K., Xiao, Y., & Liang, S. (2007). Solution structure of Jingzhaotoxin-III, a peptide toxin inhibiting both Nav1.5 and Kv2.1 channels. ''Toxicon, 50'', 135-143.Rong, M., Chen, J., Tao, H., Wu, Y., Jiang, P., Lu, M., Su, H., Chi, Y., Cai, T., Zhao, L., Zeng, X., Xiao, Y., & Liang, S. (2011). Molecular basis of the tarantula toxin jingzhaotoxin-III (TRTX-Cj1) interacting with voltage sensors in sodium channel subtype Nav1.5. The FASEB Journal, 25, 3177-3185.Wang, M., Liu, Q., Luo, H., Li, J., Tang, J., Xiao, Y., & Liang, S. (2008). Jingzhaotoxin-II, a novel tarantula toxin preferentially targets rat cardiac sodium channel. '' Biochemical Pharmacology, 76'', 1716-1727Wang, M., Diao, J., Li, J., Tang, J., Lin, Y., Hu, W., Zhang, Y., Xiao, Y., & Liang, S. (2008). JZTX-IV, a unique acidic sodium channel toxin isolated from the spider Chilobrachys jingzhao. ''Toxicon, 52'', 871-880.Xiao, Y., Tang, J., Yang, Y., Wang, M., Hu, W., Xie, J., Zeng, X., & Liang, S. (2004). Jingzhaotoxin-III, a Novel Spider Toxin Inhibiting Activation of Voltage-gated Sodium Channel in Rat Cardiac Myocytes. ''The Journal of Biological Chemistry, 279'', 26220-26226.Xiao, Y., Tang, J., Hu, W., Xie, J., Maertens, C., Tygat, J., & Liang, S. (2005). Jingzhaotoxin-I, a Novel Spider Neurotoxin Preferentially Inhibiting Cardiac Sodium Channel Inactivation. ''The Journal of Biological Chemistry, 280'', 12069-12076.Xiao, Y., Li, J., Deng, M., Dai, C., & Liang, S. (2007). Characterization of the excitatory mechanism induced by Jingzhaotoxin-I inhibiting sodium channel inactivation. ''Toxicon, 50'', 507-517.Yuan, C., Yang, S., Liao, Z., & Liang, S. (2007). Effects and mechanism of Chinese Tarantula Toxins on the Kv2.1 potassium channels. ''Biochemical and Biophysical Research Communications, 352'', 799-804.Yuan, C., Liao, Z., Zeng, X., Dai, L., Kuang, F., & Liang, S. (2007). Jingzhaotoxin-XII, a gating modifier specific for Kv4.1 channels. ''Toxicon, 50'', 646-652.Zeng, X., Deng, M., Lin, Y., Yuan, C., Pi, J., & Liang, S. (2007). Isolation and characterization of Jingzhaotoxin-V, a novel neurotoxin from the venom of the spider Chilobrachys jingzhao. ''Toxicon, 49'', 388-399.

Target

Jingzhaotoxins can target multiple channels. The following

IC50 The half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function. IC50 is a quantitative measure that indicates how much of a particular inhibitory substance ...

values have been determined: '*' Only a

dissociation constant In chemistry, biochemistry, and pharmacology, a dissociation constant (K_D) is a specific type of equilibrium constant that measures the propensity of a larger object to separate (dissociate) reversibly into smaller components, as when a complex fa ...

(Kd) was measured. Kd; 0.43 μM '**' Only a Kd was measured. Kd; 1.28 μM '***' Only a Kd was measured. Kd; 0.74 μM

Mode of action

JZTX-I

Effect on voltage-gated sodium channels (VGSC) JZTX-I preferentially acts on cardiac sodium channels, but also affects

tetrodotoxin Tetrodotoxin (TTX) is a potent neurotoxin. Its name derives from Tetraodontiformes, an order that includes pufferfish, porcupinefish, ocean sunfish, and triggerfish; several of these species carry the toxin. Although tetrodotoxin was discovered ...

-sensitive (TTX-S) voltage-gated

sodium channels Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the chann ...

(VGSC) in

dorsal root ganglion A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dorsa ...

(DRG) neurons. It modifies the sodium current by inhibiting channel inactivation and speeding up recovery after inactivation. JZTX-I does not affect the activation threshold of sodium channels. Effect on

potassium channels Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...

JZTX-I has a modest effect on potassium currents by slowing the rate of activation of Kv2.1 and Kv4.1 channels and increasing the tail current deactivation.

JZTX-II

Effect on VGSC JZTX-II has high affinity to the tetrodotoxin-resistant (TTX-R) VGSC in cardiac myocytes where it significantly slows rapid inactivation. Although JZTX-II does not have an effect on TTX-R neuronal channels in DRG neurons it does affect TTX-S sodium currents by slowing down their inactivation. Effect on potassium channels At this point, the effects of JZTX-II on potassium channels are unknown.

JZTX-III

Effect on VGSC JZTX-III has a high affinity to the TTX-R Nav1.5 voltage gated sodium channel which is expressed in cardiac myocytes but not in neurons. It modifies the sodium channel current by shifting its activation curve to a more

depolarized In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...

voltage without affecting its inactivation curve. JZTX-II is docked to the Nav1.5 DIIS3-4 linker, which is responsible for its high selectivity. Effect on potassium channels JZTX-III modifies the voltage gated Kv2.1 potassium channel in

cardiac myocytes Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate Muscle tissue, muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striat ...

and can bind to both open and closed channels. It modifies the gating of Kv2.1 channel by shifting the activation curve to a more depolarized voltage and by speeding up deactivation.

JZTX-IV

Effect on VGSC JZTX-IV acts on TTX-S sodium channels in DRG neurons by weakly reducing peak amplitudes and by obviously slowing inactivation kinetics. In contrast, JZTX-IV acts on TTX-R sodium channels on cardiac myocytes by obviously reducing its peak current and by weakly slowing inactivation kinetics. Additionally, JZTX-IV shifts the steady-state inactivation curve on both receptors. Even at high concentrations, JZTX-IV does not have any effect on TTX-R sodium channels on rat DRG neurons or on TTX-S sodium channels on hippocampal neurons. Effect on potassium channels At this point, the effects of JZTX-IV on potassium channels are largely unknown.

JZTX-V

Effect on VGSC JZTX-V has a high affinity to the resting closed state of TTX-R (Nav1.8 Nav1.9) and TTX-S (Nav1.6, Nav1.7) VGSC in DRG neurons. It modifies the sodium channel current by shifting its activation curve to a more depolarized voltage and its inactivation curve to a more hyperpolarized voltage. This means that the toxin-bound sodium channel will open at a more positive membrane potential and closes at a more negative

membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...

. Effect on potassium channels JZTX-V mainly affects the Kv4.2 potassium channel current by shifting its activation curve to a more depolarized direction and, at high concentrations, by speeding up deactivation.

JZTX-IX

Effect on VGSC JZTX-IX act on both TTX-R and TTX-S channels by shifting their activation state to a more depolarized voltage. In addition it captures the sodium channels at a closed state which speeds up inactivation. Effect on potassium channels JZTX-IX affects only the Kv2.1 channel by shifting its activation curve to a more depolarized voltage.

JZTX-XI

Effect on VGSC JZTX-XI reduces the peak sodium current amplitude of sodium channels expressed in cardiac myocytes and slows down current inactivation. JZTX-XI shows no effects on both TTX-R and TTX-S sodium currents in dorsal root ganglion neurons Effect on potassium channels JZTX-XI shifts the activation curve of Kv2.1 to a more depolarized voltage and speeds up its deactivation.

JZTX-XII

Effect on VGSC At this point, the effects of JZTX-XII on sodium channels are largely unknown. Effect on potassium channels JZTX-XII specifically acts on Kv4.1 potassium channels. It modulates potassium current by shifting Kv4.1 activation to more depolarized voltages and by producing a concentration-dependent slowing of activation and inactivation kinetics.

JZTX-34

Effect on VGSC JZTX-34 inhibits TTX-S sodium currents, but has no effect on TTX-R sodium currents. JZTX-34 does not affect activation/inactivation kinetics nor does it affect recovery rate from inactivation. Effect on potassium channels At this point, the effects of JZTX-34 on potassium channels are largely unknown.

Toxicity

The crude venom of Chilobrachys Jingzhao is lethal to mice with an intraperitoneal

LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the ...

of 4.4 mg/kg. The scarce LD50 values that have been described for the toxins that make up the venom vary; 0.23 mg/kg (JZTX-IX) – 1.48 mg/kg (JZTX-I).

References

{{reflist, 30em Neurotoxins Ion channel toxins Spider toxins