Irina Vetter

Followers

Following

Co-authors

Public Views

Manuel Hernández Fernández

Universidad Complutense de Madrid

Sedercor Melatunan

Plymouth University

Amanda Agnew

The Ohio State University

Adriana Jerez

Universidad Nacional de Colombia

Dennis V. Umali

University of the Philippines Los Baños

Khaled Qudah

Jordan University of Science and Technology

Ying Ying Leung

Duke-NUS Graduate Medical School

Alberto Sabbioni

Università degli Studi di Parma (Italy)

Ruth Ochia

Temple University

Dragos Simandan

Brock University

Interests

Uploads

Papers by Irina Vetter

Chemical engineering of the α-scorpion toxin OD1 provides selective ligands for the voltage-gated sodium channel Nav1. 7

Discovery of novel, neuronal cell-activating peptides in conotoxins

Characterizing response properties of cutaneous nociceptors using in vitro skin-nerve preparations

by Irina Vetter and Katharina Zimmermann

Ciguatoxin-Induced Release of Neuropeptides in a Sensory Neuron-Keratinocyte Coculture Model

Venoms-based drug discovery: bioassays, electrophysiology, high-throughput screens and target identification

Effets de la ciguatoxine P-CTX-2 sur la liberation induite de neuropeptides dans un modele de co-culture keratinocytes-neurones sensoriels

Toxicology of Ciguatoxins

Does Nature do Ion Channel Drug Discovery Better than Us?

Download

Ciguatera toxins: pharmacology, toxicology and detection

by Irina Vetter and Katharina Zimmermann

MrIC, a novel α-conotoxin agonist in the presence of PNU at endogenous α7 nicotinic acetylcholine receptors

α-Conotoxins are competitive antagonists of nicotinic acetylcholine receptors (nAChRs). Their hig... more α-Conotoxins are competitive antagonists of nicotinic acetylcholine receptors (nAChRs). Their high selectivity and affinity for the various subtypes of nAChRs have led to significant advances in our understanding of the structure and function of these key ion channels. Here we report the discovery of a novel 4/7 α-conotoxin, MrIC from the venom duct of Conus marmoreus, which acts as an agonist at the endogenous human α7 nAChR in SH-SY5Y cells pretreated with PNU120596 (PNU). This unique agonist activity of MrIC at α7 nAChRs may guide the development of novel α7 nAChR modulators.

Download

Multiple actions of φ-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins

An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Na v 1.6 in peripheral pain pathways

Cold allodynia, pain in response to cooling, occurs during or within hours of oxaliplatin infusio... more Cold allodynia, pain in response to cooling, occurs during or within hours of oxaliplatin infusion and is thought to arise from a direct effect of oxaliplatin on peripheral sensory neurons. To characterize the pathophysiological mechanisms underlying acute oxaliplatin-induced cold allodynia, we established a new intraplantar oxaliplatin mouse model that rapidly developed long-lasting cold allodynia mediated entirely through tetrodotoxin-sensitive Nav pathways. Using selective inhibitors and knockout animals, we found that Nav1.6 was the key isoform involved, while thermosensitive transient receptor potential channels were not involved. Consistent with a crucial role for delayed-rectifier potassium channels in excitability in response to cold, intraplantar administration of the K(+)-channel blocker 4-aminopyridine mimicked oxaliplatin-induced cold allodynia and was also inhibited by Nav1.6 blockers. Intraplantar injection of the Nav1.6 activator Cn2 elicited spontaneous pain, mechanical allodynia, and enhanced 4-aminopyridine-induced cold allodynia. These findings provide behavioural evidence for a crucial role of Nav1.6 in multiple peripheral pain pathways including cold allodynia.

Chemical engineering and structural and pharmacological characterization of the α-scorpion toxin OD1

Scorpion α-toxins are invaluable pharmacological tools for studying voltage-gated sodium channels... more Scorpion α-toxins are invaluable pharmacological tools for studying voltage-gated sodium channels, but few structure−function studies have been undertaken due to their challenging synthesis. To address this deficiency, we report a chemical engineering strategy based upon native chemical ligation. The chemical synthesis of α-toxin OD1 was achieved by chemical ligation of three unprotected peptide segments. A high resolution X-ray structure (1.8 Å) of synthetic OD1 showed the typical βαββ α-toxin fold and revealed important conformational differences in the pharmacophore region when compared with other αtoxin structures. Pharmacological analysis of synthetic OD1 revealed potent α-toxin activity (inhibition of fast inactivation) at Na v 1.7, as well as Na v 1.4 and Na v 1.6. In addition, OD1 also produced potent β-toxin activity at Na v 1.4 and Na v 1.6 (shift of channel activation in the hyperpolarizing direction), indicating that OD1 might interact at more than one site with Na v 1.4 and Na v 1.6. Investigation of nine OD1 mutants revealed that three residues in the reverse turn contributed significantly to selectivity, with the triple OD1 mutant (D9K, D10P, K11H) being 40-fold more selective for Na v 1.7 over Na v 1.6, while OD1 K11V was 5fold more selective for Na v 1.6 than Na v 1.7. This switch in selectivity highlights the importance of the reverse turn for engineering α-toxins with altered selectivity at Na v subtypes.

Download

A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases

by Kate Schroder, Luke O'Neill, Irina Vetter, and Kingston Mills

Nature Medicine, 2015

Ciguatera fish poisoning: A first epidemic in Germany highlights an increasing risk for European countries

by Irina Vetter and Katharina Zimmermann

Toxicon, 2014

Toxin-producing microalgae are thriving worldwide due to coral reef destruction and global warmin... more Toxin-producing microalgae are thriving worldwide due to coral reef destruction and global warming with major consequences on ecosystems, international trade and human health. Microalgae belonging to the family of flagellate protists, in particular dinoflagellates, secrete a variety of high-molecular-weight polyether toxins that accumulate through the marine food chain to cause disease in humans by acting as sodium channel activator toxins; ciguatera is the most frequent seafood-borne illness worldwide with 50,000 to 500,000 global incidences per annum and is usually limited to endemic areas located between 35° northern and 35° southern latitude. The rising global incidence frequency renders it a major human health problem, because no curative treatment is available yet and reliable detection assays are lacking. During the last decade ciguatera has increasingly become endemic in previously unaffected areas for two reasons: first global warming has contributed to the emergence of dinoflagellate species in subtropical and even temperate regions that previously had been constrained to tropical areas and second: in Europe globalization of fishing industry and tourism has led to a progressive increase in the number of ciguatera cases and a lack of awareness among medical personnel contributes to under-reporting. We review, through a recent ciguatera outbreak in Germany, the risk for ciguatera poisoning in Europe and highlight characteristic symptoms, current knowledge about disease pathomechanisms and treatment options.

Vergiftung durch Tropenfisch: Ciguatera-Epidemie in Deutschland

by Irina Vetter and Katharina Zimmermann

DMW - Deutsche Medizinische Wochenschrift, 2015

Ciguatera is a seafood-borne illness caused by consumption of tropical fish contaminated with cig... more Ciguatera is a seafood-borne illness caused by consumption of tropical fish contaminated with ciguatoxins, lipophilic polyethers that are produced in benthic dinoflagellates and accumulate through the marine food chain. Ciguatera cases in Europe usually occur in travellers returning from tropical and subtropical regions of the Pacific and Carribean, where ciguatera is endemic. In 2012, several cases of ciguatera occurred in Germany due to sale of contaminated fish products originating from the Indian Ocean. Although the symptomatology in these cases were typical of ciguatera, with patients reporting gastrointestinal discomfort including nausea, vomiting and diarrhea as well as neurological effects including widespread intense pruritus, paresthesias, hypothermia or altered temperature sensation and diffuse pain, correct diagnosis was delayed in all cases due to lack of awareness of the treating medical practitioners. In light of increasing global mobility, trade, and occurrence of ciguatoxic fish in previously non-endemic areas, ciguatera should be considered as a possible diagnosis if gastrointestinal and neurological symptoms occur shortly after consumption of fish.

Evolution of separate predation- and defence-evoked venoms in carnivorous cone snails

by Deon Venter and Irina Vetter

Nature Communications, 2014

Venomous animals are thought to inject the same combination of toxins for both predation and defe... more Venomous animals are thought to inject the same combination of toxins for both predation and defence, presumably exploiting conserved target pharmacology across prey and predators. Remarkably, cone snails can rapidly switch between distinct venoms in response to predatory or defensive stimuli. Here, we show that the defence-evoked venom of Conus geographus contains high levels of paralytic toxins that potently block neuromuscular receptors, consistent with its lethal effects on humans. In contrast, C. geographus predationevoked venom contains prey-specific toxins mostly inactive at human targets. Predation-and defence-evoked venoms originate from the distal and proximal regions of the venom duct, respectively, explaining how different stimuli can generate two distinct venoms. A specialized defensive envenomation strategy is widely evolved across worm, mollusk and fish-hunting cone snails. We propose that defensive toxins, originally evolved in ancestral worm-hunting cone snails to protect against cephalopod and fish predation, have been repurposed in predatory venoms to facilitate diversification to fish and mollusk diets.

Download

Natural product ligands of TRP channels

Advances in Experimental Medicine and Biology, 2011

Natural product ligands have contributed significantly to the deorphanisation of TRP ion channels... more Natural product ligands have contributed significantly to the deorphanisation of TRP ion channels. Furthermore, natural product ligands continue to provide valuable leads for the identification of ligands acting at &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;orphan&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; TRP channels. Additional naturally occurring modulators at TRP channels can be expected to be discovered in future, aiding in our understanding of not only their pharmacology and physiology, but also the therapeutic potential of this fascinating family of ion channels.

Venom peptides as a rich source of Cav2.2 channel blockers

Toxins, 2013

Ca v 2.2 is a calcium channel subtype localized at nerve terminals, including nociceptive fibers,... more Ca v 2.2 is a calcium channel subtype localized at nerve terminals, including nociceptive fibers, where it initiates neurotransmitter release. Ca v 2.2 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 Ca v 2.2 are analgesic. Venomous animals, such as cone snails, spiders, snakes, assassin bugs, centipedes and scorpions are rich sources of remarkably potent and selective Ca v 2.2 inhibitors. However, side effects in humans currently limit their clinical use. Here we review Ca v 2.2 inhibitors from venoms and their potential as drug leads.

Download

Expression and Pharmacology of Endogenous Cav Channels in SH-SY5Y Human Neuroblastoma Cells

PLoS ONE, 2013

SH-SY5Y human neuroblastoma cells provide a useful in vitro model to study the mechanisms underly... more SH-SY5Y human neuroblastoma cells provide a useful in vitro model to study the mechanisms underlying neurotransmission and nociception. These cells are derived from human sympathetic neuronal tissue and thus, express a number of the Ca v channel subtypes essential for regulation of important physiological functions, such as heart contraction and nociception, including the clinically validated pain target Ca v 2.2. We have detected mRNA transcripts for a range of endogenous expressed subtypes Ca v 1.3, Ca v 2.2 (including two Ca v 1.3, and three Ca v 2.2 splice variant isoforms) and Ca v 3.1 in SH-SY5Y cells; as well as Ca v auxiliary subunits a 2 , c 1 , c 4-5 , and c 7 . Both high-and low-voltage activated Ca v channels generated calcium signals in SH-SY5Y cells. Pharmacological characterisation using v-conotoxins CVID and MVIIA revealed significantly (, 10-fold) higher affinity at human versus rat Ca v 2.2, while GVIA, which interacts with Ca v 2.2 through a distinct pharmacophore had similar affinity for both species. CVID, GVIA and MVIIA affinity was higher for SH-SY5Y membranes vs whole cells in the binding assays and functional assays, suggesting auxiliary subunits expressed endogenously in native systems can strongly influence Ca v 2.2 channels pharmacology. These results may have implications for strategies used to identify therapeutic leads at Ca v 2.2 channels.

Download

Chemical engineering of the α-scorpion toxin OD1 provides selective ligands for the voltage-gated sodium channel Nav1. 7

Discovery of novel, neuronal cell-activating peptides in conotoxins

Characterizing response properties of cutaneous nociceptors using in vitro skin-nerve preparations

by Irina Vetter and Katharina Zimmermann

Ciguatoxin-Induced Release of Neuropeptides in a Sensory Neuron-Keratinocyte Coculture Model

Venoms-based drug discovery: bioassays, electrophysiology, high-throughput screens and target identification

Effets de la ciguatoxine P-CTX-2 sur la liberation induite de neuropeptides dans un modele de co-culture keratinocytes-neurones sensoriels

Toxicology of Ciguatoxins

Does Nature do Ion Channel Drug Discovery Better than Us?

Download

Ciguatera toxins: pharmacology, toxicology and detection

by Irina Vetter and Katharina Zimmermann

MrIC, a novel α-conotoxin agonist in the presence of PNU at endogenous α7 nicotinic acetylcholine receptors

Download

Multiple actions of φ-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins

An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Na v 1.6 in peripheral pain pathways

Chemical engineering and structural and pharmacological characterization of the α-scorpion toxin OD1

Download

A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases

by Kate Schroder, Luke O'Neill, Irina Vetter, and Kingston Mills

Nature Medicine, 2015

Ciguatera fish poisoning: A first epidemic in Germany highlights an increasing risk for European countries

by Irina Vetter and Katharina Zimmermann

Toxicon, 2014

Vergiftung durch Tropenfisch: Ciguatera-Epidemie in Deutschland

by Irina Vetter and Katharina Zimmermann

DMW - Deutsche Medizinische Wochenschrift, 2015

Evolution of separate predation- and defence-evoked venoms in carnivorous cone snails

by Deon Venter and Irina Vetter

Nature Communications, 2014

Download

Natural product ligands of TRP channels

Advances in Experimental Medicine and Biology, 2011

Venom peptides as a rich source of Cav2.2 channel blockers

Toxins, 2013

Download

Expression and Pharmacology of Endogenous Cav Channels in SH-SY5Y Human Neuroblastoma Cells

PLoS ONE, 2013

Download

Irina Vetter

Related Authors

Uploads

Papers by Irina Vetter

Log In