Environmental Causes of Dermatitis

Joao Paulo Niemeyer-Corbellini , ... Stephen K. Tyring , in Tropical Dermatology (Second Edition), 2017

Clinical Features

Most tarantula bites do not produce severe systemic toxicity, but bites can be associated with severe local pain. Bleeding from the puncture wounds may also occur. Although reports of severe human toxicity are rare, dogs bitten by Phlogellius and Selenocosmia spiders often die.

Many species of tarantula possess urticating hairs on their dorsal abdomen. These hairs are used in a defensive fashion to drive predators from the spider's burrow. Urticating hairs form a characteristic dorsal patch on the abdomen. Vibrations of the hindlegs are used to flick hairs at the perceived attacker. Itching at the site of hair penetration may persist for several weeks after exposure. Urticating hairs are absent on most African and Asian species.

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Arachnids☆

Paul A. Selden , in Reference Module in Life Sciences, 2017

Mygalomorphae

Mygalomorphs include the tarantulas or baboon spiders (Theraphosidae), trapdoor spiders (Ctenizidae, Actinopodidae, Migidae, etc.), purse-web spiders (Atypidae), funnel-web spiders (Hexathelidae), and several other families with no common name. Mygalomorphs number 16 families and 2853 species, but several of the families are para- or polyphyletic. A more realistic estimate is 20–30 family-level groups. Like mesotheles, mygalomorphs tend to live in burrows and forage at the burrow entrance or for a very limited distance around it. Some theraphosids are arboreal and weave elaborate silken retreats. Diplurids weave extensive sheet webs with their elongated spinnerets, but are unique among mygalomorphs in this respect. The venomous Australian funnel-web spiders ( Atrax and Hadronyche: Hexathelidae) were responsible for many deaths until an antivenin was developed in the 1980s. The large theraphosid baboon spiders are not seriously venomous to humans, despite their popular reputation.

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Bites and stings

Shawn M. Varney MD, FACEP , in Emergency Medicine Secrets (Fifth Edition), 2011

Arachnida (chiggers. scabies, scorpions, and spiders)

1.

What is a tarantula?

It is a large spider of the family Theraphosidae. The largest is the South American Grammostola mollicoma, with a leg span of up to 27 cm and a body length of up to 10 cm! Not much is known about tarantula venom, although it seems to contain a mixture of hyaluronidase, nucleotides, and polyamines (which act as neurotransmitters to paralyze the prey). On the whole, these bites tend to be of low toxicity in humans with a mild, briefly active venom causing pain, numbness, and lymphangitis. The bites usually do not cause necrosis or serious sequelae. The spider has little urticating hairs that are barbed and can cause skin and mucous membrane irritation with edema and pruritus that can last for weeks. Eye exposure can cause a severe keratoconjunctivitis and ophthalmia nodosa.

2.

What spider bites are likely to be an issue?

Although all spiders possess venom, there are two spiders of particular clinical importance in the United States: Latrodectus (black widow) and Loxosceles (brown recluse or fiddle back). In 2007, the American Association of Poison Control Centers (AAPCC) reported 2,514 bites from Latrodectus and 1,783 from Loxosceles. There were no deaths and only 16 major reactions attributed to Latrodectus bites (0.64%). Similarly, no deaths and 15 major reactions (0.84%) were attributed to Loxosceles. The envenomation syndromes (and treatment) of these two spiders are quite distinct (Table 71-1).

3.

What is Mustov's disease?

It is a play on words. Although there were 13,479 bites attributed to spiders reported to the AAPCC in 2007, this number is likely an inaccurate estimate of the true incidence because:

■

These are only the cases that were reported to poison control centers.

■

The effect of Mustov's disease (as in, "Doc, I woke up with this. I must've been bitten by a spider in my sleep."). It seems that a number of nonbite skin lesions (especially community acquired methicillin-resistant Staphylococcus aureus abscesses) are unfairly blamed on spiders. Mustov's disease is not specific to spider bites.

4.

A 5-year-old boy presents with genital itching that started several hours after sitting on the lawn watching a fireworks display. His examination reveals intensely pruritic, erythematous papules around his groin. What is this? How can it be treated? (Clue: he had been wearing shorts.)

Chiggers. They are tiny mite larvae that cause intense pruritus. The diagnosis is based on identifying the characteristic skin lesions in a person with an outdoor exposure. Itching begins within a few hours of exposure, and the papules can enlarge to form nodules in 1 to 2 days. There may be fever and erythema multiforme. Treatment is with antihistamines and steroids (topical or oral) for the symptoms, and lindane, permethrin, or crotamiton for definitive therapy.

5.

What are the distinguishing features of scabies?

The bites are typically in the web spaces between the fingers and toes (also the penis, face, and scalp in children). They create burrows of pruritic, white, threadlike patterns with small gray spots at the closed end, where the parasite rests. Treatment is with a thorough application of permethrin from the neck down and may require a second course of treatment in 2 weeks.

6.

How dangerous are scorpion stings?

Scorpions are generally not aggressive. They do not hunt for prey, but rather hide and wait. Scorpions have paired venom glands located in the last of the five abdominal segments (the tail). They hold their prey with their pincers, arch their tail over their body, and sting (not bite) the victim. The principal toxins are polypeptides and low-molecular-weight proteins, histamine, and indole compounds (including serotonin). The venom causes an increase in the sodium permeability of presynaptic neurons, which leads to continuous depolarization. Most scorpions indigenous to the United States are of low toxicity except for the bark scorpion (Centruroides). In North America, Centruroides exilicauda (found in Baja California) and Centruroides sculpturatus (in Sonora, Mexico, and in the Southwestern U.S.—Arizona, Utah, New Mexico, Nevada, and California) are capable of producing systemic toxicity. They can hitch a ride in unsuspecting travelers' luggage. In 2007, the AAPCC reported 16,937 patients with scorpion stings. There was moderate morbidity in 3.9% of patients, major morbidity in 0.18%, and no deaths.

7.

What are the signs of scorpion envenomation?

The sting is acutely painful. Systemic manifestations are rare and mainly occur in small children and the elderly where a larger venom-to-body weight ratio exists. The principal signs of systemic toxicity are salivation, tachycardia, roving eye movements, involuntary muscle jerking, opisthotonos, and tongue fasciculations.

8.

What is the treatment for a scorpion sting?

Supportive care with local wound care, analgesia, and benzodiazepines for the neuromuscular symptoms is the mainstay of treatment. There was a Centruroides scorpion antivenom available only in Arizona, but it is no longer produced. A new scorpion-specific fragment antigen binding (Fab) F(ab)2 antivenom (Anascorp™) is available in Mexico and is undergoing evaluation in the United States. In critically ill children with neurotoxic effects the antivenom has been shown to resolve the clinical syndrome within 4 hours, to reduce the need for concomitant sedation with benzodiazepines, and to reduce the levels of circulating unbound venom.

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The International Trade in Insects and Terrestrial Arthropods

Scott A. Elias , in Reference Module in Earth Systems and Environmental Sciences, 2021

Tarantula spiders

Tarantulas have been popular pets ever since international air travel (both passenger service and air-mail package transport) enabled the trade, starting in the 1960s. According to a study of the tarantula pet trade ( Trumpness, 2014), there are three kinds of tarantula owners. First are the Collectors. These are people who accumulate tarantulas the same way other people collect stamps. Collectors amass and display large collections of spiders. Collections over 50 specimens are quite common. They spend significant sums on their hobby but are not particularly enamored of their specimens. Rather, they usually view the animals with scientific detachment or regard them as curiosities.

The second group is the Enthusiasts. Tarantula enthusiasts have a real passion for the hobby. They are extremely active on social media, engaging with other enthusiasts on the care and feeding of their spiders. The internet has provided an ideal outlet for their enthusiasm, offering related online tarantula owner chat rooms, and online sales outlets.

The third kind of tarantula owner is the Dedicated Pet Owner. These people take their pet ownership responsibilities and obligations very seriously. They do their homework before making a purchase. They often keep only one tarantula, and give it a pet name, rather than call it by its scientific classification. They love their tarantula, even if it is a one-sided relationship.

Tarantula species that are most popular as pets include the Pinktoe tarantulas (Avicularia urticans, A. avicularia, Achorutes aurantica), the Costa Rican Zebra (Aphonopelma seemanni), the Honduran curly hair (Brachypelma albopilosum), Mexican redknee/leg/red rumps (Brachypelma smithi, Brachypelma emilia, B. vagans), the Trinidad chevron (Psalmopoeus cambridgei), African baboons (Hysterocrates sp.), the Orange blue bottle (Chromatopelma cyaneopubescens), Brazilian whiteknee (Acanthoscurria geniculata), and the Chilean rose hair (Phrixotrichus spatulata), which is the most common spider in pet stores. The prices of these tarantulas, either online or in pet stores, range from a low of $20 for specimens of A. seemanni, B. albopilosum, and B. vagans, to prices as high as $350–$450 for female specimens of B. smithi, B. emilia, and A. geniculata.

Hazards of tarantula ownership

All spiders have venomous bites. No known tarantulas have bites that kill people unless the victim has a severe allergy to a particular venom. However, as described by Rayor (2021), even seemingly calm tarantula species that are considered "handleable" may become aggressive and bite if threatened. Tarantulas have relatively small venom glands only in their chelicerae, as opposed to glands that extend into their cephalothorax. Chelicerae are a pair of appendages in front of the mouth in arachnids. The bite of most species is described as being similar to a bee sting. On the other hand, tarantula fangs are some of the largest of all spiders, so even if they fail to inject their victims with lethal doses of venom, significant injuries can be sustained from a tarantula bite. Their fangs are easily strong enough to break the skin and penetrate some depth into your flesh!

In addition to venomous bites, New World tarantulas have another very effective defense mechanism. When threatened, they quickly scrape especially irritating hairs, called urticating hairs, from the back and sides of their abdomens into the eyes, nose, or lungs of their vertebrate predators. The hairs have a variety of shapes and are coated with irritating chemicals that cause itchy skin or irritated membranes. When these hairs get in people's eyes, surgery is sometimes required to have them removed. This is the most serious risk likely to be experienced from owning a tarantula. Some species are more likely than others to flick hairs.

Tarantula smuggling

As reviewed by DeMio (2020) there is now a multibillion-dollar, worldwide trade in tarantulas. These days there are far too few specimens available through legal channels, so they are being systematically hunted down, smuggled out of their home countries, and sold as pets to people who will pay hundreds of dollars for a single spider. Tarantulas are desirable for their color, size, rarity, uniqueness, and longevity in captivity. Males generally live only a few years at most since their sole aim is to breed with a female. But females of some species can live 30  years or more. This makes them far more attractive as pets, so tarantula hunters usually seek out adult females, digging them out of crevices or burrows in their native habitats, mostly in tropical forests. This harvesting wreaks havoc on both the spiders and their homes. Although they look very hardy and robust because of their hairy covering, tarantulas actually have rather thin, breakable exoskeletons. This makes even live specimens prone to injury or death during collection or transport. As Rayor (2021) put it, "if dropped, they tend to splat and bleed to death." Egg sacs are often thrown away, killing 100–1500 developing spiderlings.

One example of demand exceeding the legal supply of tarantulas comes from Mexico. Licensed breeders of species of Brachypelma in Mexico report that they collectively produce an average of 11,000–14,000 juvenile tarantulas annually (West and Cooper, 2017). All their Brachypelma specimens are sold and exported exclusively to Canadian and US tarantula dealers. But the Mexican breeders say that they have requests for Brachypelma specimens from the EU, China, and Japan that they cannot fill. Tarantula breeders and keepers suggest that the illegal trade in Brachypelma species far exceeds the legal trade. They report that large numbers of live tarantulas are smuggled out of Mexico, mainly to the EU and Asia.

Tarantula smuggling follows certain patterns. Sadly, most tropical countries that are home to the tarantula species sought by collectors are relatively poor countries with insufficient funds to operate robust wildlife protection policies. For example, Fukushima et al. (2020) discussed how tarantula trafficking has low priority for wildlife enforcement authorities in most South American countries. Specifically, loopholes in Brazilian environmental law, the permeability of Brazil's borders, and the ease of smuggling spiders internationally by sending specimens in falsely labeled packages by post also contribute to the flow of tarantulas from Brazil to other points of the world. Once out of the country, many Brazilian specimens of tarantulas are sold in the pet trade.

The spiders may be "brown-boxed," with dozens of little, padded containers, and express-mailed to Europe. These packages may be mislabeled as some kind of legal merchandise, or they may be placed inside containers of otherwise legal cargo that customs officers might ignore. They are also frequently packed in the smuggler's luggage and flown off to Europe. Europe is the destination chosen by smugglers because the European Union, unlike the United States and Canada, does not have strict laws about the import and ownership of exotic animals. Hobbyists and tarantula dealers thus flock to Europe to purchase their prized pets at tarantula trade shows. Once purchased, the contraband spiders are then smuggled back to the United States or Canada by their new owners. Smuggling tarantulas (and other arthropods) is made easier by their physiology and minimal biological requirements. Arthropods do not suffer altitude sickness because they have very low oxygen requirements when they are inactive. Adult tarantulas and scorpions can easily survive days or weeks without food or water. Relatively speaking, they are small, lightweight, and are content to sit still inside a container for great lengths of time. They don't squeak, bark, or make any other loud noises that would attract the attention of customs officers.

The following incident, told by Law and Stokstad (2019), provides a good example of the ways and means of tarantula smugglers. A previously unknown species of blue-legged tarantula was found in a tropical jungle in the Malaysian state of Sarawak in 2017. Collectors and arachnologists alike were thrilled by the discovery of the new species, but there is more to the story than meets the eye. Gabriel and Sherwood (2019) published the formal description of the new species, calling it Birupes simoroxigorum. But following this publication, the Forest Department of Sarawak said that whoever collected the new tarantula specimens lacked permits to collect or export wildlife. In short, the tarantulas were illegally smuggled out of Malaysia before two specimens ended up in the hands of the scientists. The smugglers were a group of tarantula collectors from Poland and the United Kingdom that find, breed, and sell tarantulas. They later conceded that they had no collecting permit, claiming they did not know one was required. They also insisted they did not smuggle the tarantulas out of Malaysia, saying their driver mailed the spiders to Europe. Sarawak Wildlife officials hope to get the three collectors banned from reentering the island.

Spiderlings, immature spiders, are favored by both smugglers and dealers because they live longer and they are more difficult to identify, making it hard for wildlife officials to determine their country of origin. Likewise, it is also hard to prove that such specimens are not multi-generation captive-bred tarantulas.

A total of 23 species of tarantulas are listed for protection from over-exploitation by CITES. These include Mexican species: the Golden Red Rump Tarantula (Aphonopelma albiceps), the Rose Tarantula (Aphonopelma pallidum), and all 18 species of red-legged tarantulas in the genus Brachypelma. The other tarantula listed by CITES is the Indian ornamental tree spider (Poecilotheria spp.) that lives in India and Sri Lanka (CITES, 2021).

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Ion Channels DownUnder

Lachlan D. Rash , in Advances in Pharmacology, 2017

3.4 Selective Modulators: ASIC1a Inhibitors (Table 2)

PcTx1 is a 40-amino acid, inhibitor-cystine knot peptide isolated from tarantula venom and was the first highly potent and selective ASIC1a inhibitor discovered ( Escoubas et al., 2000). Although used as a selective inhibitor of ASIC1a homomers, it also inhibits heteromeric ASIC1a/ASIC2 channels (Joeres, Augustinowski, Neuhof, Assmann, & Grunder, 2016; Sherwood, Lee, Gormley, & Askwith, 2011) and potentiates homomeric ASIC1b currents (Chen, Kalbacher, & Grunder, 2006). Given that ASIC1b does not appear to be expressed in the brain or spinal cord, PcTx1 remains a highly useful tool for studying the contribution of ASIC1a in the CNS. PcTx1 has been cocrystalized with cASIC1 (Baconguis & Gouaux, 2012), and several structure–activity studies carried out using rat ASIC1a (Saez et al., 2011, 2015). These studies demonstrate that PcTx1 binds predominantly to α-helix 5 in the thumb domain with its positively charged β-hairpin loop poking into the acidic pocket (Fig. 1B), thereby stabilizing ASIC1a in its desensitized state (Chen, Kalbacher, & Gründer, 2005).

The mambalgins are a family of three-finger peptides isolated from the venom of several mamba snake (Dendroaspis) species. They are selective for ASIC1, with highest potency (~   10   nM) and 100% efficacy at inhibiting ASIC1a (Diochot et al., 2012). The mambalgin-binding site overlaps that of PcTx1 at the acidic pocket (Salinas et al., 2014; Schroeder et al., 2014); however, unlike PcTx1 (which induces desensitization) they appear to inhibit ASIC channel activation by stabilizing the closed state (Salinas et al., 2014). The substantial difference in mechanism and subtype selectivity, relative to PcTx1, makes the mambalgins invaluable tools for structure–function studies of ASIC1.

Of the five NSAIDs found to modulate ASIC function, flurbiprofen and ibuprofen are not particularly potent (IC50 ~   350   μM) but appear to be quite selective for ASIC1a (Voilley et al., 2001). The NSAIDs probably inhibit ASICs via open channel block but do not compete with amiloride (Dorofeeva, Barygin, Staruschenko, Bolshakov, & Magazanik, 2008), thus may define a novel modulatory site in the channel pore making them useful tools to understand new regulatory-binding sites. The antimalarial drug chloroquine (also used in rheumatoid arthritis) is toxic to the retina, a fact that led to the discovery of its ASIC1a inhibitory activity (IC50 ~   600   μM) (Li et al., 2014). Sinomenine is an alkaloid from a climbing plant (Sinomenium acutum) used in Chinese medicine to treat arthritis and neuralgia. Its traditional therapeutic use in pain and inflammation and the discovery that sinomenine is a potent blocker of ASIC1a (~   1   μM IC50), as well as having substantial neuroprotective effects in cerebral ischemia (Wu et al., 2011), makes it a very interesting tool for further study. It appears that chloroquine and sinomenine have so far only been tested on ASIC1a; therefore, their subtype selectivity and mechanism of action are unknown. Unlike the local anesthetics tetracaine and propofol, which are largely nonselective in their effects on ASICs, lidocaine inhibited heterologously expressed ASIC1a (IC50 ~   12   mM) without affecting ASIC2a currents, however, was not tested on ASIC3 (Lin et al., 2011).

PPC-5650 is claimed to be a selective ASIC1a inhibitor (IC50 ~   500   nM) and was a novel drug candidate for a small biotech company called Painceptor. This drug was tested in a small human trial for analgesic activity (UV sunburn model) and showed promising effects (Dube et al., 2009); however, there is not much available data demonstrating its ASIC subtype selectivity, binding site, or mechanism of action. PPC-5650 has recently resurfaced, being tested in two more experimental human pain models (rectal and esophageal pain), where it was reasonably well tolerated but only mildly efficacious in the esophageal model but not in the rectal model (Nielsen et al., 2015; Olesen, Nielsen, Larsen, & Drewes, 2015). Until more is reported on the ASIC activity of this compound, its value as a research tool is unclear.

NS383 is a small molecule drug lead from the Danish company NeuroSearch and was identified using a fluorescence-based screen against human ASIC1a (Munro et al., 2016). It has potent and relatively selective ASIC1a inhibitory activity (IC50 0.44   μM vs 2.1   μM for ASIC3 homomers) and also potently blocks currents in cells coexpressing ASIC1a and ASIC3 with little apparent effect on ASIC2a, and unknown activity at ASIC1b. The inhibitory activity of NS383 is apparent during coapplication with low pH and is strongly pH-dependent suggesting competition with protons, thus it may have a novel mechanism of action. NS383 had effective analgesic activity in both inflammatory and neuropathic rodent pain models with no obvious motor impairment when delivered intraperitoneally. Consistent with this, NS383 was found to be very selective for ASICs in an off-target screen making this a promising new therapeutic lead and valuable tool to study ASICs in vivo.

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Thermal Sensors

Jie Zheng , Linlin Ma , in Current Topics in Membranes, 2014

3.4 Toxin binding

A fortunate discovery for the TRPV1 research field is the identification of a peptide toxin from tarantula spider venom that acts as a potent channel agonist ( Bohlen et al., 2010; Siemens et al., 2006). The high (submicromolar) apparent affinity of the double-knot toxin, DkTx, is partially a consequence of the divalent design, as binding of one knot substantially enhances the binding of the second knot through enhancement of the effective local concentration (Bohlen et al., 2010). Judging from the elicited currents or intracellular Ca2+ change, DkTx is almost as potent as capsaicin in activating rodent TRPV1. Mutagenesis analysis suggested that the outer pore region participates in toxin binding/potentiation. This was confirmed by the cryo-EM study, which revealed that the toxin binds to the outer pore region between subunits (Cao et al., 2013; Liao et al., 2013). The channel/DkTx complex (also contained the potent activator RTX) revealed the conformation of a likely open channel. Comparison with the apo structure suggests that activation conformational changes are mostly limited to the pore domains, involving expansion of both the S6 gate and the selectivity filter gate. It is interesting to note that the binding of capsaicin alone is capable of inducing the S6 gate opening. The binding of DkTx clearly induced substantial rearrangements of the outer pore structures. It remains unclear whether the difference in the S6 gate conformations between the DkTx/RTX-bound structure and the capsaicin-bound structure is due to DkTx or RTX.

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Voltage-Gated Channels

Edward C. Conley , in Ion Channel Factsbook: Voltage-Gated Channels, 1999

A new class of peptide inhibitors of Kv2 family channels

49-43-01: rKv2.1/DRK1 : Two peptides isolated from the venom of a Chilean tarantula, hanatoxin1 (HaTx1) and hanatoxin2 (HaTx2), unrelated in primary sequence to other K+ channel-selective toxins have been described 78 as 'selective' blockers of Kv2 subfamily channels. Shaker-related, Shaw-related, and eag K+ channels are relatively insensitive to HaTx. Regions outside the scorpion toxin binding site (S5–S6 linker) determine sensitivity to HaTx. Prior to the hanatoxins, no potent (or selective) blockers were available for Kv2 subfamily channels. Typically, 50% inhibitory concentrations (IC50) for 'classical' K+ channel blockers include 4-aminopyridine (4-AP, 0.5   mm, see next paragraph); tetraethylammonium ions, TEA+ (10   mm) 5 . Kv2.1 in oocytes is insensitive to Co2+ (≥2   mm), Cd2+ (>0.2   mm), apamin (≥1 m) and CTx (≥1 m). 'High-millimolar' intracellular Mg2+and Na+ has been reported to induce inward rectification (for brief description, see Current-voltage relation, 49-35. rKv2.2/CDRK1: TEA IC50 ~7.9± 1.7   mm (mean SEM, n = 5) 11 .

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Globins and Other Nitric Oxide-Reactive Proteins, Part B

Luca Ronda , ... Andrea Mozzarelli , in Methods in Enzymology, 2008

6 DETERMINATION OF OBCS FOR HEMOCYANIN IN SOLUTION AND IN SILICA GELS

As an example of the potentiality of this novel apparatus, the measurement of OBCs for the nonheme-containing protein hemocyanin from the tarantula Eurypelma californicum (Decker et al., 1988), both in solution and encapsulated in silica gels, is described. In order to isolate the quaternary conformations of hemocyanin, the 24-meric giant protein was encapsulated in wet, nanoporous silica gels, either in the absence or in the presence of oxygen. Spectra of hemocyanin in solution (Fig. 16.6A) and in gels (not shown) were collected at oxygen pressures between 0 and 760 torr, pH 7.0, at 4°. Because the visible spectrum of deoxygenated hemocyanin is featureless (see Figs. 16.6A and 16.6B), fractional saturations were calculated from the intensity at 340   nm of the Cu2-O2 absorption band. OBCs measured on the deoxy- and oxy-encapsulated protein (see Fig. 16.6B) exhibit a Kavg of 0.09 ± 0.02 and 0.40 ± 0.16   torr−1, respectively, in close agreement with the affinity calculated for hemocyanin in solution at low and high oxygen pressures. The observed Hill coefficients, 0.72 ± 0.11 and 0.82 ± 0.05 for deoxy- and oxyhemocyanin gels, respectively, are significantly lower than unity, indicating a conformational heterogeneity within each locked conformational state, a finding in agreement with the assumption that at least four conformational states are required to explain the oxygen-binding properties of E. californicum hemocyanin in solution (Ronda et al., 2007).

Figure 16.6. OBCs for E. californicum hemocyanin in solution and in silica gel. (A) Spectra of hemocyanin in solution, in 50   mM Bis-Tris propane, 50   mM Tris, 5   mM MgCl2, 5   mM CaCl2, pH 7.0, at 4°, recorded at increasing oxygen pressures between 0 and 760   torr. (B) The OBC for hemocyanin in solution (open circles) was analyzed according to the MWC model (Monod et al., 1965), leading to a KT of 0.10 ± 0.01   torr−1, KR of 0.75 ± 0.36   torr−1 OBCs for hemocyanin encapsulated in deoxy (filled squares) and oxy (filled circles) conformations, analyzed assuming two independent binding sites, gave an averaged K of 0.09 ± 0.02 and 0.40 ± 0.16   torr−1, respectively.

Overall, key features of the setup described are the (i) accuracy in the determination of OBCs using either a conventional spectrophotometer or a microspectrophotometer; (ii) easy generation of complex gas mixtures, containing up to four components, with also very dilute components; (iii) flexibility of recording OBCs on both soluble and immobilized samples, with measuring fields of a few micrometers; (iv) precise multiwavelength evaluation of the fractional saturation, taking into account sample damaging due, for example, to oxidation.

We are currently developing a fully automatized system for the determination of OBCs for heme and nonheme proteins operating in either a "static" or a "dynamic" mode. In this case, a thin layer of a sample solution is placed in a modified sample holder within the gas-tight flow cell on the microspectrophotometer stage. By controlling the gas mixture preparation, the timing of the delivery, and the spectra recording simultaneously, OBCs can be determined under easily adjustable conditions.

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Kv4 Voltage Gated Potassium Channel

Dirk Isbrandt , ... Licher Thomas , in xPharm: The Comprehensive Pharmacology Reference, 2007

Ligands, Substrates, Ions

Ligands

4-Aminopyridine (4-AP; general, relatively non-specific A-type channel antagonist); various Kv4-specific tarantula toxins: e.g., Heteropodatoxin (HpTx), Phrixotoxin (PaTx), Stromatopelmatoxin (ScTx) and Theraphosatoxin (TLTx).

Ions

Value Units Reference Remarks
Potassium
Biophysics Multi-exponential inactivation with τ1 = 11 ms (73% of total decay), τ2 = 50 ms (23% of total decay) and τ3 = 700 ms (4% of total decay); Onset of closed-state inactivation with τ = 1 s at-60 mV; Recovery from inactivation with τ = 250 ms at-80 m V. (Whole-cell patch-clamp data from hKv4.2 in HEK 293 expression system; similar data have been obtained for Kv4.2 and for Kv4.1 and Kv4.3 in Xenopus oocytes) Bähring et al (2001a), Jerng and Covarrubias (1997), Jerng et al (1999). Fast activation already below action potential firing threshold; rapid inactivation with multiple components; accumulation in closed-inactivated states at all relevant voltages. Fast and voltage-dependent recovery from inactivation. Accessory KChIPs slow the onset of and enhance the recovery from inactivation; DPPX accelerates current decay.
Conductance 1.8, 3.4 and 5.7 pS Beck et al (2002) mKv4.1: Various subconductance states; not influenced by accessory KChIPs
Voltage Dependence hKv4.1: V1/2act-7 (16), V1/2inact-65 (9) mV Bähring et al (2001b), Beck et al (2002), Nadal et al (2003) V1/2 values for activation and steady-state inactivation (the latter more negative!), respectively. Slope-factors are given in brackets. The voltage dependence may be influenced by accessory KChIPs and DPPX.
Voltage Dependence hKv4.2: V1/2act-1 (16), V1/2inact-57 (5) mV Bähring et al (2001b), Beck et al (2002), Nadal et al (2003) V1/2 values for activation and steady-state inactivation (the latter more negative!), respectively. Slope-factors are given in brackets. The voltage dependence may be influenced by accessory KChIPs and DPPX.
Voltage Dependence hKv4.3: V1/2act-4 (17), V1/2inact-55 (5) mV Bähring et al (2001b), Beck et al (2002), Nadal et al (2003) V1/2 values for activation and steady-state inactivation (the latter more negative!), respectively. Slope-factors are given in brackets. The voltage dependence may be influenced by accessory KChIPs and DPPX.

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CNS, Pain, Metabolic Syndrome, Cardiovascular, Tissue Fibrosis and Urinary Incontinence

P. Beswick , in Comprehensive Medicinal Chemistry III, 2017

7.03.5.4 Cav2.3 Blockers

There have been recent reports which suggest that Cav2.3 plays a role in pain signaling and that this channel might also be a pain target. 14 Validation data comes from studies with the tarantula toxin SNX-482 demonstrating efficacy in preclinical pain models. 205 It important to highlight that while SNX-482 selectively blocks Cav2.3 channels it does have some activity at Cav1 channels. Mice lacking the Cav2.3 gene demonstrate reduced sensitivity to pain, 206 and clinically it has been suggested that polymorphisms of the gene may be responsible for different responses to fentanyl in patients undergoing surgery. 14 Currently no selective small-molecule Cav2.3 inhibitors have been reported. There are publications showing that drugs such as lamotrigine and topiramate block Cav2.3 in addition to other channels. 14

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