Helothermine (or HLTx) is a toxin from the venom of the Mexican

beaded lizard The Mexican beaded lizard (''Heloderma horridum'') is a species of lizard in the Family (biology), family Helodermatidae, one of the two species of venomous beaded lizards found principally in Mexico and southern Guatemala. It and congener (biolo ...

''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.

Etymology

The name of the toxin helothermine is derived from its source, a

Heloderma ''Heloderma'' is a genus of toxicoferan lizards that contains five species, all of which are venomous. It is the only extant genus of the family Helodermatidae. Description The genus ''Heloderma'' contains the Gila monster (''H. suspectum'') a ...

lizard, and one of its effects in mice, induction of hypothermia.

Sources

Helothermine is a toxin found in the venom (salivary secretion) of the Mexican beaded lizard ''Heloderma horridum horridum'', one of the four subspecies of the

. Besides helothermine the venom of the Mexican beaded lizard also contains at least three other toxins and several enzymes.

Chemistry

The peptide HLTx consists of 242 amino acids residues in a single polypeptide chain. It is stabilized with eight disulfide bridges and has a molecular weight of 25.5 kDa. The iso-electric point is 6.8 and the N-terminal amino acid sequence is: Glu-Ala-Ser-Pro-Lys-Leu-Pro-Gly-Leu-Met-Thr-Ser-Asn-Pro-Asp-Gln-Gln-Thr- Glu-Ile. HLTx shows no structural similarities with any of the known sodium-, potassium- or calcium channel-specific toxins. Highest similarities are found with a family of cysteine-rich secretory proteins (CRISP), found in human and in mice testes.

Target and mode of action

HLTx inhibits ryanodine receptors of sarcoplasmic reticulum and both

calcium channel A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, although there are also ligand-gated calcium channels. Comparison tables The following tables e ...

s and

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 ...

Calcium channels

The effects of HLTx on voltage-dependent calcium channels have been tested in granule cells of the cerebellum. In these cells, HLTx inhibits up to 67% of the calcium currents, acting on multiple subtypes. This inhibition is reversible, concentration-dependent and practically voltage-independent. No effects on the activation and inactivation kinetics were observed. A small shift in the steady-state inactivation curve has been reported.

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 ...

is 0.25 μM.

Potassium Channels

HLTx inhibits both delayed rectifier and A-type potassium channels in cerebellar granular cells. HLTx reduces the A-type current in a voltage and concentration-dependent way, with an IC50 of 0.52 μM. It slows down both the activation and the inactivation kinetics of the A-type current. The block of the delayed-rectifier current is not voltage-dependent, but only concentration-dependent, with an IC50 of 0.83 μM.

Ryanodine receptor

The ryanodine receptor, both in skeletal and in cardiac sarcoplasmic reticulum (SR), is inhibited by HLTx. The affinity of the toxin is much higher for the skeletal- than for the cardiac SR receptors, but binding is reversible in both cases.

Toxicity

The main effect of HTLx seems to be the induction of

hypothermia Hypothermia is defined as a body core temperature below in humans. Symptoms depend on the temperature. In mild hypothermia, there is shivering and mental confusion. In moderate hypothermia, shivering stops and confusion increases. In severe h ...

. Other effects are lethargy, intestinal distension/diarrhea and paralysis of the rear limbs. Sporadic tonic convulsions can occur when the intoxicated animals are touched on the dorsal parts of their body. The specific toxins of the Mexican beaded lizard are probably evolved to immobilize preys, as these lizards move very slowly themselves.

References

J. Mochca-Morales, B.M. Martin, L.D. Possani, 1990, Isolation and characterization of helothermine, a novel toxin from ''Heloderma horridum horridum'' (Mexican beaded lizard) venom, Toxicon, 28 (3), 299-309 M.E. Adams and G. Swanson, 1994, Neurotoxins, Trends in Neurosciences, 17:1s-28s J. Morrissette et al, 1995, Primary structure and properties of Helothermine, a peptide toxin that blocks ryanodine receptors, Biophys. J, 68(6): 2280-8 M. Nobile et al, 1996, Helothermine, a lizard venom toxin, inhibits calcium current in cerebellar granules, Exp Brain Res, 110:15-20 M.Nobile et al, 1994, the toxin HLTx affects potassium currents in newborn rat cerebellar granule cells, J. Membrane Biology, 139: 49-55 {{Reflist Neurotoxins Ion channel toxins Lizard toxins Calcium channel blockers Potassium channel blockers