Ssm6a (''Scolopendra subspinipes mutilans'' 6), or μ-SLPTX-Ssm6a, is a toxin from the
venom of the
Chinese red-headed centipede. It has strong analgesic properties, probably owing to its strong inhibitory effects on
Nav1.7 channels.
Sources
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 is composed of 46 amino acids. It is the result of
posttranslational modification of a
prepropeptide
A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein (or peptide) that can be turned into an active form by post-translational modification, such as breaking off a piece of the molecule or adding on another molecule ...
. 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 a propeptide sequence. The 46 C-terminal amino acids are the Ssm6a peptide.
Structure
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 an
inhibitor cystine knot, commonly found in invertebrate toxins.
Stability and Specificity
Ssm6a is quite resistant to
proteases in human blood and it remains stable under high temperatures. This stability is due to the primarily alpha-helical structure and three disulfide bonds.
Target
Ssm6a has a strong inhibitory effect on
Nav1.7 channels (
IC50=25.4 nM). It has a less potent inhibitory effect on
Nav1.1 (IC50=4.1 μM),
Nav1.2 (IC50=813 nM) or on
Nav1.6
Sodium channel protein type 8 subunit alpha also known as Nav1.6 is a membrane protein encoded by the ''SCN8A'' gene. Nav1.6 is one sodium channel isoform and is the primary voltage-gated sodium channel at each node of Ranvier. The channels are hi ...
channels (IC50=15.2 μM).
Recent reports have not been able to verify the Nav1.7 specific activity which has been claimed in the original publication.
Mode of action
The inhibitory effect of Ssm6a on NaV channels can be partly overcome by a higher depolarization,
suggesting that Ssm6a is a gating modifier that interacts with the voltage-sensing domains of voltage-dependent sodium channels.
Therapeutic use
Nav1.7 channels are present at the endings of pain-sensing nerves. These channels are key components in
nociception
Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the sensory nervous system's process of encoding noxious stimuli. It deals with a series of events and processes required for an organism to receive a painful stimulus, co ...
. 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
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
properties, and apparent lack of side effects.
Recent reports have not been able to verify the Nav1.7 specific activity which has been claimed in the original publication.
References
{{Reflist
Ion channel toxins