Helothermine is a toxin from the venom of the Mexican beaded lizard

Beaded lizard

The Beaded lizard is a species of venomous lizard found principally in Mexico and southern Guatemala. Along with its congener, the Gila monster , it is the only lizard to have evolved an overt venom delivery system, and has long been considered the only venomous 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.

Etymology

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

Heloderma

Heloderma, the only genus of the family Helodermatidae, consists of venomous lizards native to the southwestern United States, Mexico and as far south as Guatemala. It includes two separate species, with six subspecies...

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

Source

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 beaded lizard

Beaded lizard

The Beaded lizard is a species of venomous lizard found principally in Mexico and southern Guatemala. Along with its congener, the Gila monster , it is the only lizard to have evolved an overt venom delivery system, and has long been considered the only venomous lizard...

. 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 cysteïne-rich secretory proteins (CRISP), found in human and in mice testes.

Target and mode of action

HLTx inhibits ryanodine receptor

Ryanodine receptor

Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...

s of sarcoplasmatisch reticulum and both calcium channel

Calcium channel

A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...

s and potassium channel

Potassium channel

In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...

s.

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

IC50

The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance is needed to inhibit a given biological process by half...

 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 sarcoplasmatic 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

Hypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...

. 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.