Abstract
Cav2.2 is a calcium channel subtype localized at nerve terminals, including nociceptive fibers, where it initiates neurotransmitter release. Cav2.2 is an important contributor to synaptic transmission in ascending pain pathways, and is up-regulated in the spinal cord in chronic pain states along with the auxiliary α2δ1 subunit. It is therefore not surprising that toxins that inhibit Cav2.2 are analgesic. Venomous animals, such as cone snails, spiders, snakes, assassin bugs, centipedes and scorpions are rich sources of remarkably potent and selective Cav2.2 inhibitors. However, side effects in humans currently limit their clinical use. Here we review Cav2.2 inhibitors from venoms and their potential as drug leads.
Highlights
A wide diversity of venomous animals has evolved a large range of peptide toxins that target ion channels expressed in the neuronal and neuromuscular systems of prey and predators as part of efficient prey immobilization and deterrent strategies
Spider venom peptides with activity at Cav2.2 have to date only been described from Haplopelma huwenum, Agelenopsis aperta, Phoneutria nigriventer, Phoneutria reidyi and Segestria florentina [7,110,111,112,113,114,115,116,117,118,119,120,121,122,123]
Ptu1 lacks most of the residues shown to be important for ω-conotoxin binding to the N-type calcium channel, including equivalents of Tyr13 or Lys2 (Figures 4 and 5). This peptide belongs to the inhibitory cysteine knot structural family (ICK) that consists of a four-loop Cys scaffold forming a compact disulfide-bonded core [142]
Summary
A wide diversity of venomous animals has evolved a large range of peptide toxins that target ion channels expressed in the neuronal and neuromuscular systems of prey and predators as part of efficient prey immobilization and deterrent strategies. Many of the most selective ion channel modulators known originate from venoms (reviewed by [1]). These peptide toxins have evolved from a relatively small number of structural frameworks that are well suited to address crucial issues such as, potency and stability [1]. A range of disulfide rich peptides from cone snails (conotoxins) preferentially inhibit. MVIIA (ziconotide, Prialt®), from the venom of the cone snail Conus magus is currently in use clinically, validating Cav2.2 as an analgesic target in humans [15,18]. We review Cav2.2 channel inhibitor toxins from venoms, their pharmacological and structural properties as well as their therapeutic potential
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