A Tale of Toxin Promiscuity: The Versatile Pharmacological Effects of Hcr 1b-2 Sea Anemone Peptide on Voltage-Gated Ion Channels

Abstract

Sea anemones are a rich source of biologically active compounds. Among approximately 1100 species described so far, Heteractis crispa species, also known as sebae anemone, is native to the Indo-Pacific area. As part of its venom components, the Hcr 1b-2 peptide was first described as an ASIC1a and ASIC3 inhibitor. Using Xenopus laevis oocytes and the two-electrode voltage-clamp technique, in the present work we describe the remarkable lack of selectivity of this toxin. Besides the acid-sensing ion channels previously described, we identified 26 new targets of this peptide, comprising 14 voltage-gated potassium channels, 9 voltage-gated sodium channels, and 3 voltage-gated calcium channels. Among them, Hcr 1b-2 is the first sea anemone peptide described to interact with isoforms from the Kv7 family and T-type Cav channels. Taken together, the diversity of Hcr 1b-2 targets turns this toxin into an interesting tool to study different types of ion channels, as well as a prototype to develop new and more specific ion channel ligands.

Nicotinic Acetylcholine Receptors Are Novel Targets of APETx-like Toxins from the Sea Anemone Heteractis magnifica

“…For the electrophysiological experiments, toxin Hmg 1b-2 (=Hcr 1b-2) was chosen. This toxin was studied by us not only as ASICs’ inhibitor [ 16 ], but it also displayed an exceptional lack of selectivity, from the 28 tested voltage gated cation channels, comprising 16 potassium (K V ), 9 sodium (Na V ), and 3 calcium (Ca V ) channels, 26 of them were subject to a certain degree of activation or inhibition by this toxin [ 33 ]. Despite such promiscuity to ion channels, this toxin exhibited an antihyperalgesic effect in the model of acid-induced muscle pain [ 16 ] and weak anxiolytic activity in the open field and elevated plus maze tests, wherein it did not demonstrate any toxic action or stimulating effects on the central nervous system [ 34 ].…”

“…It is still unclear if Hmg 1b-2 is an allosteric, orthosteric or combined ligand, but its effects on cholinergic response could be compared with the action of positive allosteric modulators such as α-conotoxin MrIC, and protein lynx-1 [ 36 , 37 , 38 ]. It should be noted that, based on our previous observation of the potentiating and inhibitory effects of APETx-like peptides on their targets [ 16 , 17 , 22 , 33 ], both agonists and antagonists might be found among these toxins.…”

“…Finally, peptide APETx4 was an inhibitor of several Na V and K V channels including the subtype hEag1 [ 50 ]. The APETx-like peptides Hcr 1b-1–Hcr 1b-4 turned out to be the modulators of ASIC1a and ASIC3 channels [ 16 , 17 ], while Hcr 1b-2 inhibited in sum 23 subtypes of Na V , K V , and Ca V channels as well as potentiate K V 1.1, K V 1.2, and Shaker channels [ 33 ], as noted above.…”

Pharmacological Screening of Venoms from Five Brazilian Micrurus Species on Different Ion Channels

“…For example, voltage-gated potassium channels (K V s) [ 70 , 71 ] and voltage-gated sodium channels (Na V s) [ 70 , 72 ] are objects of study in high incidence diseases such as cancer and neurodegenerative disorders [ 73 , 74 , 75 , 76 ], and so, are explored as therapeutical targets [ 77 , 78 , 79 , 80 ]. Toxins from sea anemone, scorpions, spiders, cone snails, centipedes and snakes are being investigated in studies with K V and Na V [ 65 , 67 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. Therefore, in general, animal toxins are of pharmacological interest in the studies using voltage-gated ion channels.…”

Mechanisms of Action of the Peptide Toxins Targeting Human and Rodent Acid-Sensing Ion Channels and Relevance to Their In Vivo Analgesic Effects

“…Hcr 1b-4 was found to be the first potentiator of ASIC3, simultaneously inhibiting rASIC1a at similar concentrations, with an EC 50 of 1.53 μM and an IC 50 of 1.25 μM, respectively. Hcr1b-2 showed an analgesic activity in vivo, significantly reducing the number of writhings in an acetic acid-induced writhing test, but promiscuous effects were also reported for Hcr1b-2 (1µM), mostly inhibiting but also potentiating Kv, Nav and Cav (T type) channels [ 167 ].…”