A recent study has suggested that a substance called Hm-3, which is derived from crab spider toxin, may pave the way for new treatments for a subtype of the rare neuromuscular disorder, primary periodic paralysis (PPP). The study was published online on April 24, 2018 in the Proceedings of the National Academy of Sciences of the United States of America.1 “We propose that Hm-3 and similar toxins may constitute useful hits in developing gating pore current inhibitors and HypoPP therapy,” wrote first author Roope Männikkö, PhD, of UCL Institute of Neurology (London, UK), and colleagues.
HypoPP, or hypokalemic periodic paralysis, is characterized by low potassium levels that cause episodic muscle weakness. Patients with HypoPP have mutations that affect voltage sensing domains (VSDs) for specific calcium (HypoPP type 1) or sodium (HypoPP type 2) ion channels in skeletal muscle. Basically, VSDs detect cross-membrane electrical differences that trigger opening and closing of cell membrane channels. Mutations that affect VSDs can cause a leak current (ie, leakage of ions), across the cell membrane, leading to depolarization of the cell membrane and muscle symptoms.
The primary intervention for hypoPP is avoidance of triggers and treatment with carbonic anhydrase inhibitors. But these medications sometimes have no effect on HypoPP or can paradoxically worsen symptoms in some patients. Scientists are looking for better medications that may address the underlying pathophysiology of these diseases.
One line of investigation involves toxins that target ion channels by binding to specific sites on VSDs, effectively blocking the leak current that leads to symptoms. Past studies have suggested that toxin from the Heriaeus melloteei crab spider, called Hm-3, might be a viable candidate for development. Crab spiders are a type of spider (not crab) comprising over 2000 different species found all over the world.
To test Hm-3, scientists did a series of in vitro experiments to see if Hm-3 could block the abnormal leak current, which showed that Hm-3 does in fact block the abnormal current. Next, they tested whether Hm-3 has a specific binding site on the abnormal VSDs involved in the leak current. Testing Hm-3 on four different mutant ion channels showed that it did not block the abnormal current in three out of four of them. However, the fact that it blocked the current in one of the ion channels suggested that Hm-3 may have a specific binding site. Futher analysis with magnetic resonance (NMR) spectroscopy revealed that Hm-3 probably has a specific binding site on the abnormal VSD in HypoPP type 2.
Taken together, these findings suggest that Hm-3 blocks the abnormal current caused by mutations in a type of VSD that causes HypoPP type 2, and that Hm-3 has a specific binding site on this particular VSD. Unfortunately, results also showed that Hm-3 may block normal sodium channels, which may limit its clinical usefulness. Still, the results are promising because they suggest that toxins like Hm-3 may lay the groundwork for new agents that are more selective toward the abnormal leak current in HypoPP, without affecting normal channels.
Take Home Points
• Findings from in vitro experiments suggest that Hm-3, derived from crab spider toxin, blocks the abnormal leak current caused by mutations that depolarize the cell membrane and cause muscular symptoms in Hypo-PP type 2 (caused by mutations affecting sodium channels)
• Hm-3 also blocked normal sodium channels, limiting its clinical usefulness
• Results may lay the groundwork for developing more selective agents that target the pathophysiology of PPP
1. Männikkö R, Shenkarev ZO, Thor MG, et al. Spider toxin inhibits gating pore currents underlying periodic paralysis. Proc Natl Acad Sci USA. 2018;115:4495-4500.