Pain-related toxins in scorpion and spider venoms: a face to face with ion channels

Abstract

Pain is a common symptom induced during envenomation by spiders and scorpions. Toxins isolated from their venom have become essential tools for studying the functioning and physiopathological role of ion channels, as they modulate their activity. In particular, toxins that induce pain relief effects can serve as a molecular basis for the development of future analgesics in humans. This review provides a summary of the different scorpion and spider toxins that directly interact with pain-related ion channels, with inhibitory or stimulatory effects. Some of these toxins were shown to affect pain modalities in different animal models providing information on the role played by these channels in the pain process. The close interaction of certain gating-modifier toxins with membrane phospholipids close to ion channels is examined along with molecular approaches to improve selectivity, affinity or bioavailability in vivo for therapeutic purposes.

Venom Peptide Toxins Targeting the Outer Pore Region of Transient Receptor Potential Vanilloid 1 in Pain: Implications for Analgesic Drug Development

“…Peptide toxins can modulate TRPV1 activation by binding to specific domains, including the outer pore domain [ 6 ]. Various peptide toxins directly inhibit or activate this channel by binding to sites in the outer pore domain involved in the channel’s gating mechanism [ 90 , 91 ]. In particular, some toxins, including DxTx, BmP01, and RhTx, have been shown to activate or inhibit TRPV1 by binding to the outer pore domain of the channels ( Figure 1 ) [ 6 , 90 , 91 ].…”

“…Various peptide toxins directly inhibit or activate this channel by binding to sites in the outer pore domain involved in the channel’s gating mechanism [ 90 , 91 ]. In particular, some toxins, including DxTx, BmP01, and RhTx, have been shown to activate or inhibit TRPV1 by binding to the outer pore domain of the channels ( Figure 1 ) [ 6 , 90 , 91 ]. This implies that the outer pore region of TRPV1 is a common domain for binding and channel gating by different peptide animal toxins and highlights the importance of the outer pore domain in TRPV1 activation [ 36 ].…”

Venom-derived pain-causing toxins: insights into sensory neuron function and pain mechanisms

“…Although spider envenomation commonly results in localized pain, most spider peptides studied to date block Na V and Ca V channels and therefore act to inhibit neuronal excitability. 34,35,52 This however is almost certainly a reflection of "discovery bias" because most spider venom-screening efforts have focused on finding inhibitors of key analgesic targets, such as Na V 1.7 and Ca V 2.2. 47,69,118 Nevertheless, several spider venom-derived peptides with algogenic activity have provided crucial insights into the structure and function of TRPV1 and Na V channels, and these are discussed in greater detail below.…”

Transcriptome analysis of the spider Phonotimpus pennimani reveals novel toxin transcripts

“…Toxins are bioactive peptides that act with high affinity and specificity on various molecular targets, among them ion channels [ 20 , 21 ]. These peptides can have a neurotoxic, cardiotoxic, antimicrobial, antifungal, or enzymatic action, can produce paralysis or death, and can aid prey digestion [ 22 ]. Considering the number of spider species and data from the mass spectrometric analysis of venoms, spiders may produce an estimated 2-20 million peptides [ 20 , 23 , 24 ].…”