Isolation, synthesis and characterization of ω-TRTX-Cc1a, a novel tarantula venom peptide that selectively targets L-type CaV channels

Klint, Julie K.; Berecki, Géza; Durek, Thomas; Mobli, Mehdi; Knapp, Oliver; King, Glenn F.; Adams, David J.; Alewood, Paul F.; Rash, Lachlan D.

doi:10.1016/j.bcp.2014.02.008

Cited by 20 publications

(26 citation statements)

References 50 publications

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“…Synthetic Pre1a was assembled manually using Boc SPPS chemistry as described previously 56 . The side-chain protecting groups chosen were Asn (Xan), Arg (Tos), Asp (OcHex), Cys (4-MeBzl), Lys (ClZ), Ser (Bzl), Trp (CHO) and Tyr (BrZ).…”

Section: Methodsmentioning

confidence: 99%

The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity

Wingerd

Mozar

Ussing

et al. 2017

Sci Rep

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Voltage-gated sodium (NaV) channels are essential for the transmission of pain signals in humans making them prime targets for the development of new analgesics. Spider venoms are a rich source of peptide modulators useful to study ion channel structure and function. Here we describe β/δ-TRTX-Pre1a, a 35-residue tarantula peptide that selectively interacts with neuronal NaV channels inhibiting peak current of hNaV1.1, rNaV1.2, hNaV1.6, and hNaV1.7 while concurrently inhibiting fast inactivation of hNaV1.1 and rNaV1.3. The DII and DIV S3-S4 loops of NaV channel voltage sensors are important for the interaction of Pre1a with NaV channels but cannot account for its unique subtype selectivity. Through analysis of the binding regions we ascertained that the variability of the S1-S2 loops between NaV channels contributes substantially to the selectivity profile observed for Pre1a, particularly with regards to fast inactivation. A serine residue on the DIV S2 helix was found to be sufficient to explain Pre1a’s potent and selective inhibitory effect on the fast inactivation process of NaV1.1 and 1.3. This work highlights that interactions with both S1-S2 and S3-S4 of NaV channels may be necessary for functional modulation, and that targeting the diverse S1-S2 region within voltage-sensing domains provides an avenue to develop subtype selective tools.

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Section: Methodsmentioning

confidence: 99%

The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity

Wingerd

Mozar

Ussing

et al. 2017

Sci Rep

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“…The C-terminus of ω-TRTX-Pm1a was found to be critical for its activity: a C-terminally truncated analogue was almost inactive on both Ca V and Na V channels [28]. Similarly, we found that the activity of Mb1a/1b was influenced by the C-terminal region, with the putative native toxin, Mb1a, being more potent at inhibiting Ca V channels than Mb1b.…”

Section: Discussionmentioning

confidence: 69%

“…The closest homologues of Mb1a and-Mb1b are the spider toxins ω-TRTX-Hg1a (71% identity) [25,26], β-TRTX-Cm2a (68% identity) [27] and ω-TRTX-Pm1a (68% identity) [28] (Figure 10), all of which are active on vertebrate voltage-gated ion channels. None of these toxins have been tested against insects.…”

Section: Discussionmentioning

confidence: 99%

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Insect-Active Toxins with Promiscuous Pharmacology from the African Theraphosid Spider Monocentropus balfouri

Smith

Herzig

Ikonomopoulou

et al. 2017

Toxins

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Many chemical insecticides are becoming less efficacious due to rising resistance in pest species, which has created much interest in the development of new, eco-friendly bioinsecticides. Since insects are the primary prey of most spiders, their venoms are a rich source of insect-active peptides that can be used as leads for new bioinsecticides or as tools to study molecular receptors that are insecticidal targets. In the present study, we isolated two insecticidal peptides, µ/ω-TRTX-Mb1a and -Mb1b, from venom of the African tarantula Monocentropus balfouri. Recombinant µ/ω-TRTX-Mb1a and -Mb1b paralyzed both Lucilia cuprina (Australian sheep blowfly) and Musca domestica (housefly), but neither peptide affected larvae of Helicoverpa armigera (cotton bollworms). Both peptides inhibited currents mediated by voltage-gated sodium (NaV) and calcium channels in Periplaneta americana (American cockroach) dorsal unpaired median neurons, and they also inhibited the cloned Blattella germanica (German cockroach) NaV channel (BgNaV1). An additional effect seen only with Mb1a on BgNaV1 was a delay in fast inactivation. Comparison of the NaV channel sequences of the tested insect species revealed that variations in the S1–S2 loops in the voltage sensor domains might underlie the differences in activity between different phyla.

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“…diltiazem) [14, 16-18]. Recently, ω-TRTX-Cc1a, derived from the venom of the tarantula Citharischius crawshayi (now Pelinobius muticus ), turned out to be a potent and selective blocker of Ca v 1.2 and Ca v 1.3 Ca 2+ channels [19]. Experimental activators of L-type channels include BayK8644, FPL64176, PCA50941 and SZ(+)-(S)-202-791, none of which is however used in clinical application settings [20].…”

Section: Structure Function and Pharmacology Of Voltage-gated Ca2+ Cmentioning

confidence: 99%

Review: Cav2.3 R-type Voltage-Gated Ca2+ Channels - Functional Implications in Convulsive and Non-convulsive Seizure Activity

Wormuth¹,

Lundt²,

Henseler³

et al. 2016

TONEUJ

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Background:Researchers have gained substantial insight into mechanisms of synaptic transmission, hyperexcitability, excitotoxicity and neurodegeneration within the last decades. Voltage-gated Ca2+ channels are of central relevance in these processes. In particular, they are key elements in the etiopathogenesis of numerous seizure types and epilepsies. Earlier studies predominantly targeted on Cav2.1 P/Q-type and Cav3.2 T-type Ca2+ channels relevant for absence epileptogenesis. Recent findings bring other channels entities more into focus such as the Cav2.3 R-type Ca2+ channel which exhibits an intriguing role in ictogenesis and seizure propagation. Cav2.3 R-type voltage gated Ca2+ channels (VGCC) emerged to be important factors in the pathogenesis of absence epilepsy, human juvenile myoclonic epilepsy (JME), and cellular epileptiform activity, e.g. in CA1 neurons. They also serve as potential target for various antiepileptic drugs, such as lamotrigine and topiramate.Objective: This review provides a summary of structure, function and pharmacology of VGCCs and their fundamental role in cellular Ca2+ homeostasis. We elaborate the unique modulatory properties of Cav2.3 R-type Ca2+ channels and point to recent findings in the proictogenic and proneuroapoptotic role of Cav2.3 R-type VGCCs in generalized convulsive tonic–clonic and complex-partial hippocampal seizures and its role in non-convulsive absence like seizure activity.Conclusion:Development of novel Cav2.3 specific modulators can be effective in the pharmacological treatment of epilepsies and other neurological disorders.

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Isolation, synthesis and characterization of ω-TRTX-Cc1a, a novel tarantula venom peptide that selectively targets L-type CaV channels

Cited by 20 publications

References 50 publications

The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity

The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity

Insect-Active Toxins with Promiscuous Pharmacology from the African Theraphosid Spider Monocentropus balfouri

Review: Cav2.3 R-type Voltage-Gated Ca2+ Channels - Functional Implications in Convulsive and Non-convulsive Seizure Activity

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