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Special Issue "Marine Drugs and Ion Currents"

A special issue of Marine Drugs (ISSN 1660-3397).

Deadline for manuscript submissions: closed (31 May 2017)

Special Issue Editors

Guest Editor
Dr. Elisabetta Tosti

Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, 8012, Naples, Italy
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Phone: +39 081 5833288
Fax: +39 081 7641355
Interests: marine animals; reproduction; fertilization; ion currents; environmental stress
Guest Editor
Dr. Alessandra Gallo

Department of Biology and Evolution of Marine Organisms, Stazione Zoologica Anton Dohrn, 8012, Naples, Italy
Website | E-Mail
Interests: marine animals; reproduction; fertilization; ion currents; evironmental stress

Special Issue Information

Dear Colleagues

The cell plasma membrane marks the border between the cytoplasm and the external environment. This compartmentalization is essential for cell activity and viability and is regulated by specific dynamics of ion current fluxes through the cell. Main ions such as potassium (K+), sodium (Na+) and calcium (Ca2+) cations are differentially distributed inside and outside the cell, giving rise to an electrical gradient across the membrane known as a voltage. Ion currents flow through ion channels, specific proteins inserted into the plasma membrane. These are characterized by their specificity, gating, and sensitivity to drugs, and mainly open in response to a ligand or a change in voltage. It is known that marine-derived compounds act on a series of biological processes. The scope of this Special Issue is to provide information on marine natural products whose target are the ion currents playing roles in key physiological processes. Here, toxin structure, function, mechanism of action and potential clinical and technological application will be reported.

Dr. Elisabetta Tosti
Dr. Alessandra Gallo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Marine Drugs is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ion currents
  • Ion channels
  • Calcium channels
  • Sodium channels
  • Potassium channels
  • Marine natural products
  • Toxins

Published Papers (7 papers)

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Research

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Open AccessArticle Ciguatoxins Evoke Potent CGRP Release by Activation of Voltage-Gated Sodium Channel Subtypes NaV1.9, NaV1.7 and NaV1.1
Mar. Drugs 2017, 15(9), 269; doi:10.3390/md15090269
Received: 22 June 2017 / Revised: 4 August 2017 / Accepted: 16 August 2017 / Published: 30 August 2017
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Abstract
Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel
[...] Read more.
Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals. In this study, we used mouse and rat skin preparations and enzyme-linked immunosorbent assays (ELISA) to study the molecular mechanism by which P-CTX-1 induces CGRP release. We show that P-CTX-1 induces CGRP release more effectively in mouse as compared to rat skin, exhibiting EC50 concentrations in the low nanomolar range. P-CTX-1-induced CGRP release from skin is dependent on extracellular calcium and sodium, but independent from the activation of various thermosensory transient receptor potential (TRP) ion channels. In contrast, lidocaine and tetrodotoxin (TTX) reduce CGRP release by 53–75%, with the remaining fraction involving L-type and T-type voltage-gated calcium channels (VGCC). Using transgenic mice, we revealed that the TTX-resistant voltage-gated sodium channel (VGSC) NaV1.9, but not NaV1.8 or NaV1.7 alone and the combined activation of the TTX-sensitive VGSC subtypes NaV1.7 and NaV1.1 carry the largest part of the P-CTX-1-caused CGRP release of 42% and 34%, respectively. Given the contribution of CGRP to nociceptive and itch sensing pathways, our findings contribute to a better understanding of sensory symptoms of acute and chronic ciguatera that may help in the identification of potential therapeutics. Full article
(This article belongs to the Special Issue Marine Drugs and Ion Currents)
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Open AccessArticle A Transcriptomic Survey of Ion Channel-Based Conotoxins in the Chinese Tubular Cone Snail (Conus betulinus)
Mar. Drugs 2017, 15(7), 228; doi:10.3390/md15070228
Received: 31 May 2017 / Revised: 10 July 2017 / Accepted: 13 July 2017 / Published: 18 July 2017
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Abstract
Conotoxins in the venom of cone snails (Conus spp.) are a mixture of active peptides that work as blockers, agonists, antagonists, or inactivators of various ion channels. Recently we reported a high-throughput method to identify 215 conotoxin transcripts from the Chinese tubular
[...] Read more.
Conotoxins in the venom of cone snails (Conus spp.) are a mixture of active peptides that work as blockers, agonists, antagonists, or inactivators of various ion channels. Recently we reported a high-throughput method to identify 215 conotoxin transcripts from the Chinese tubular cone snail, C. betulinus. Here, based on the previous datasets of four transcriptomes from three venom ducts and one venom bulb, we explored ion channel-based conotoxins and predicted their related ion channel receptors. Homologous analysis was also performed for the most abundant ion channel protein, voltage-gated potassium (Kv; with Kv1.1 as the representative), and the most studied ion channel receptor, nicotinic acetylcholine receptor (nAChR; with α2-nAChR as the representative), in different animals. Our transcriptomic survey demonstrated that ion channel-based conotoxins and related ion channel proteins/receptors transcribe differentially between the venom duct and the venom bulb. In addition, we observed that putative κ-conotoxins were the most common conotoxins with the highest transcription levels in the examined C. betulinus. Furthermore, Kv1.1 and α2-nAChR were conserved in their functional domains of deduced protein sequences, suggesting similar effects of conotoxins via the ion channels in various species, including human beings. In a word, our present work suggests a high-throughput way to develop conotoxins as potential drugs for treatment of ion channel-associated human diseases. Full article
(This article belongs to the Special Issue Marine Drugs and Ion Currents)
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Open AccessArticle Maitotoxin Is a Potential Selective Activator of the Endogenous Transient Receptor Potential Canonical Type 1 Channel in Xenopus laevis Oocytes
Mar. Drugs 2017, 15(7), 198; doi:10.3390/md15070198
Received: 5 April 2017 / Revised: 15 June 2017 / Accepted: 21 June 2017 / Published: 25 June 2017
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Abstract
Maitotoxin (MTX) is the most potent marine toxin known to date. It is responsible for a particular human intoxication syndrome called ciguatera fish poisoning (CFP). Several reports indicate that MTX is an activator of non-selective cation channels (NSCC) in different cell types. The
[...] Read more.
Maitotoxin (MTX) is the most potent marine toxin known to date. It is responsible for a particular human intoxication syndrome called ciguatera fish poisoning (CFP). Several reports indicate that MTX is an activator of non-selective cation channels (NSCC) in different cell types. The molecular identity of these channels is still an unresolved topic, and it has been proposed that the transient receptor potential (TRP) channels are involved in this effect. In Xenopus laevis oocytes, MTX at picomolar (pM) concentrations induces the activation of NSCC with functional and pharmacological properties that resemble the activity of TRP channels. The purpose of this study was to characterize the molecular identity of the TRP channel involved in the MTX response, using the small interference RNA (siRNA) approach and the two-electrode voltage-clamp technique (TEVC). The injection of a specifically designed siRNA to silence the transient receptor potential canonical type 1 (TRPC1) protein expression abolished the MTX response. MTX had no effect on oocytes, even at doses 20-fold higher compared to cells without injection. Total mRNA and protein levels of TRPC1 were notably diminished. The TRPC4 siRNA did not change the MTX effect, even though it was important to note that the protein level was reduced by the silencing of TRPC4. Our results suggest that MTX could be a selective activator of TRPC1 channels in X. laevis oocytes and a useful pharmacological tool for further studies on these TRP channels. Full article
(This article belongs to the Special Issue Marine Drugs and Ion Currents)
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Review

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Open AccessReview Guanidinium Toxins and Their Interactions with Voltage-Gated Sodium Ion Channels
Mar. Drugs 2017, 15(10), 303; doi:10.3390/md15100303
Received: 29 June 2017 / Revised: 14 September 2017 / Accepted: 27 September 2017 / Published: 13 October 2017
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Abstract
Guanidinium toxins, such as saxitoxin (STX), tetrodotoxin (TTX) and their analogs, are naturally occurring alkaloids with divergent evolutionary origins and biogeographical distribution, but which share the common chemical feature of guanidinium moieties. These guanidinium groups confer high biological activity with high affinity and
[...] Read more.
Guanidinium toxins, such as saxitoxin (STX), tetrodotoxin (TTX) and their analogs, are naturally occurring alkaloids with divergent evolutionary origins and biogeographical distribution, but which share the common chemical feature of guanidinium moieties. These guanidinium groups confer high biological activity with high affinity and ion flux blockage capacity for voltage-gated sodium channels (NaV). Members of the STX group, known collectively as paralytic shellfish toxins (PSTs), are produced among three genera of marine dinoflagellates and about a dozen genera of primarily freshwater or brackish water cyanobacteria. In contrast, toxins of the TTX group occur mainly in macrozoa, particularly among puffer fish, several species of marine invertebrates and a few terrestrial amphibians. In the case of TTX and analogs, most evidence suggests that symbiotic bacteria are the origin of the toxins, although endogenous biosynthesis independent from bacteria has not been excluded. The evolutionary origin of the biosynthetic genes for STX and analogs in dinoflagellates and cyanobacteria remains elusive. These highly potent molecules have been the subject of intensive research since the latter half of the past century; first to study the mode of action of their toxigenicity, and later as tools to characterize the role and structure of NaV channels, and finally as therapeutics. Their pharmacological activities have provided encouragement for their use as therapeutants for ion channel-related pathologies, such as pain control. The functional role in aquatic and terrestrial ecosystems for both groups of toxins is unproven, although plausible mechanisms of ion channel regulation and chemical defense are often invoked. Molecular approaches and the development of improved detection methods will yield deeper understanding of their physiological and ecological roles. This knowledge will facilitate their further biotechnological exploitation and point the way towards development of pharmaceuticals and therapeutic applications. Full article
(This article belongs to the Special Issue Marine Drugs and Ion Currents)
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Open AccessFeature PaperReview Conotoxins as Tools to Understand the Physiological Function of Voltage-Gated Calcium (CaV) Channels
Mar. Drugs 2017, 15(10), 313; doi:10.3390/md15100313
Received: 8 August 2017 / Revised: 6 September 2017 / Accepted: 4 October 2017 / Published: 13 October 2017
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Abstract
Voltage-gated calcium (CaV) channels are widely expressed and are essential for the completion of multiple physiological processes. Close regulation of their activity by specific inhibitors and agonists become fundamental to understand their role in cellular homeostasis as well as in human
[...] Read more.
Voltage-gated calcium (CaV) channels are widely expressed and are essential for the completion of multiple physiological processes. Close regulation of their activity by specific inhibitors and agonists become fundamental to understand their role in cellular homeostasis as well as in human tissues and organs. CaV channels are divided into two groups depending on the membrane potential required to activate them: High-voltage activated (HVA, CaV1.1–1.4; CaV2.1–2.3) and Low-voltage activated (LVA, CaV3.1–3.3). HVA channels are highly expressed in brain (neurons), heart, and adrenal medulla (chromaffin cells), among others, and are also classified into subtypes which can be distinguished using pharmacological approaches. Cone snails are marine gastropods that capture their prey by injecting venom, “conopeptides”, which cause paralysis in a few seconds. A subset of conopeptides called conotoxins are relatively small polypeptides, rich in disulfide bonds, that target ion channels, transporters and receptors localized at the neuromuscular system of the animal target. In this review, we describe the structure and properties of conotoxins that selectively block HVA calcium channels. We compare their potency on several HVA channel subtypes, emphasizing neuronal calcium channels. Lastly, we analyze recent advances in the therapeutic use of conotoxins for medical treatments. Full article
(This article belongs to the Special Issue Marine Drugs and Ion Currents)
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Open AccessReview µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission: A Therapeutic Potential
Mar. Drugs 2017, 15(10), 295; doi:10.3390/md15100295
Received: 28 July 2017 / Revised: 12 September 2017 / Accepted: 20 September 2017 / Published: 22 September 2017
PDF Full-text (3130 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The Conus genus includes around 500 species of marine mollusks with a peculiar production of venomous peptides known as conotoxins (CTX). Each species is able to produce up to 200 different biological active peptides. Common structure of CTX is the low number of
[...] Read more.
The Conus genus includes around 500 species of marine mollusks with a peculiar production of venomous peptides known as conotoxins (CTX). Each species is able to produce up to 200 different biological active peptides. Common structure of CTX is the low number of amino acids stabilized by disulfide bridges and post-translational modifications that give rise to different isoforms. µ and µO-CTX are two isoforms that specifically target voltage-gated sodium channels. These, by inducing the entrance of sodium ions in the cell, modulate the neuronal excitability by depolarizing plasma membrane and propagating the action potential. Hyperexcitability and mutations of sodium channels are responsible for perception and transmission of inflammatory and neuropathic pain states. In this review, we describe the current knowledge of µ-CTX interacting with the different sodium channels subtypes, the mechanism of action and their potential therapeutic use as analgesic compounds in the clinical management of pain conditions. Full article
(This article belongs to the Special Issue Marine Drugs and Ion Currents)
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Open AccessReview Ladder-Shaped Ion Channel Ligands: Current State of Knowledge
Mar. Drugs 2017, 15(7), 232; doi:10.3390/md15070232
Received: 16 June 2017 / Revised: 7 July 2017 / Accepted: 14 July 2017 / Published: 20 July 2017
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Abstract
Ciguatoxins (CTX) and brevetoxins (BTX) are polycyclic ethereal compounds biosynthesized by the worldwide distributed planktonic and epibenthic dinoflagellates of Gambierdiscus and Karenia genera, correspondingly. Ciguatera, evoked by CTXs, is a type of ichthyosarcotoxism, which involves a variety of gastrointestinal and neurological symptoms, while
[...] Read more.
Ciguatoxins (CTX) and brevetoxins (BTX) are polycyclic ethereal compounds biosynthesized by the worldwide distributed planktonic and epibenthic dinoflagellates of Gambierdiscus and Karenia genera, correspondingly. Ciguatera, evoked by CTXs, is a type of ichthyosarcotoxism, which involves a variety of gastrointestinal and neurological symptoms, while BTXs cause so-called neurotoxic shellfish poisoning. Both types of toxins are reviewed together because of similar mechanisms of their action. These are the only molecules known to activate voltage-sensitive Na+-channels in mammals through a specific interaction with site 5 of its α-subunit and may compete for it, which results in an increase in neuronal excitability, neurotransmitter release and impairment of synaptic vesicle recycling. Most marine ciguatoxins potentiate Nav channels, but a considerable number of them, such as gambierol and maitotoxin, have been shown to affect another ion channel. Although the extrinsic function of these toxins is probably associated with the function of a feeding deterrent, it was suggested that their intrinsic function is coupled with the regulation of photosynthesis via light-harvesting complex II and thioredoxin. Antagonistic effects of BTXs and brevenal may provide evidence of their participation as positive and negative regulators of this mechanism. Full article
(This article belongs to the Special Issue Marine Drugs and Ion Currents)
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