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Ssm6a (Scolopendra subspinipes mutilans 6), or μ-SLPTX-Ssm6a, is a 46-residue toxin of 5318.41 Da that has an inhibitory effect on the Nav 1.7 channel.

Source

Ssm6a is purified from the venom of the Chinese red-headed centipede, Scolopendra subspinipes mutilans, found in Southeast Asia.

Biochemistry

Family

Ssm6a is part of the scoloptoxin family (SPLTX), together with Ssm1a, Ssm2a, and Ssm3a, all found in the venom of the centipede.

Synthesis

The mature form of Ssm6a composed of 46 amino acids, is the result of posttranslational modification of a prepropeptide. This precursor is not well known in terms of structure, function and activity. The prepropeptide is 112 amino acids long. The 21 N-terminal amino acids are related to a signal sequence, the 43 following amino acids are referred as propetide sequence. Finally, the 46 C-terminal amino acids refer to the Ssm6a peptide.

Structure

Ssm6a is a unique peptide. No similar proteins have been listed in protein database (Uniprot and Swissprot), and Ssm6a shares only 40% of identity with its most related protein κ-SLPTX-Ssm1, another toxin recently isolated from the venom of the same centipede. The 3D structure analysis reveal six cysteine residues forming three disulfide bonds: Cys5–Cys32, Cys15–Cys31, Cys18–Cys41. This structure is very similar to a inhibitor cystine knot, commonly found in invertebrate toxins.

Stability

The protein showed to have very high stability. Ssm6a is quite resistant to proteases in human blood and it remains stable under high temperatures. This stability is due to the primarily alfa-helical structure and three disulfide bonds. Target Ssm6a has a strong inhibitory effect on the Nav1.7 channels (IC50=25.4 nM). It has a less inhibitory effect on Nav1.1 (IC50=4.1 µM), Nav1.2 (IC50=813 nM) and on Nav1.6 channels (IC50=15.2 µM).

Mode of action

It has been shown in vitro that the inhibitory effect of Ssm6a on NaV channels can be partly overcome by an higher depolarization. These results suggest Ssm6a is a gating modifier that interacts with the voltage-sensing domains of NaV channels.

Effects on mammals

The toxin inhibit only a few number of sodium channels. Even at a highly dose (10 time the dose required to observe analgesic effects) of Ssm6a, no side effects were observed. The maximal dose tested in rodent, 1 μmol/kg, does not cause changes in physiological constants.

Therapeutic use

Nav1.7 channels are present at the endings of pain-sensing nerves. These channels are key components in nociception. Rodent treated with Ssm6a exhibit a drastically decreased in nociceptive response. Ssm6a show a significantly higher efficiency than morphine in response to induced abdominal writhing (by injection of acid) and thermal pain (by photothermal heat). Ssm6a is now considered as a potential morphine substitute, due to its analgesic properties.