Isolation, synthesis and characterization of omega-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. and Rash, Lachlan D. (2014) Isolation, synthesis and characterization of omega-TRTX-Cc1a, a novel tarantula venom peptide that selectively targets L-type CaV channels. Biochemical Pharmacology, 89 2: 276-286. doi:10.1016/j.bcp.2014.02.008


Author Klint, Julie K.
Berecki, Géza
Durek, Thomas
Mobli, Mehdi
Knapp, Oliver
King, Glenn F.
Adams, David J.
Alewood, Paul F.
Rash, Lachlan D.
Title Isolation, synthesis and characterization of omega-TRTX-Cc1a, a novel tarantula venom peptide that selectively targets L-type CaV channels
Formatted title
Isolation, synthesis and characterization of ω-TRTX-Cc1a, a novel tarantula venom peptide that selectively targets L-type CaV channels
Journal name Biochemical Pharmacology   Check publisher's open access policy
ISSN 0006-2952
1873-2968
Publication date 2014-05-15
Sub-type Article (original research)
DOI 10.1016/j.bcp.2014.02.008
Open Access Status
Volume 89
Issue 2
Start page 276
End page 286
Total pages 11
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Collection year 2015
Language eng
Formatted abstract
Spider venoms are replete with peptidic ion channel modulators, often with novel subtype selectivity, making them a rich source of pharmacological tools and drug leads. In a search for subtype-selective blockers of voltage-gated calcium (CaV) channels, we isolated and characterized a novel 39-residue peptide, ω-TRTX-Cc1a (Cc1a), from the venom of the tarantula Citharischius crawshayi (now Pelinobius muticus). Cc1a is 67% identical to the spider toxin ω-TRTX-Hg1a, an inhibitor of CaV2.3 channels. We assembled Cc1a using a combination of Boc solid-phase peptide synthesis and native chemical ligation. Oxidative folding yielded two stable, slowly interconverting isomers. Cc1a preferentially inhibited Ba2+ currents (IBa) mediated by L-type (CaV1.2 and CaV1.3) CaV channels heterologously expressed in Xenopus oocytes, with half-maximal inhibitory concentration (IC50) values of 825 nM and 2.24 μM, respectively. In rat dorsal root ganglion neurons, Cc1a inhibited IBa mediated by high voltage-activated CaV channels but did not affect low voltage-activated T-type CaV channels. Cc1a exhibited weak activity at NaV1.5 and NaV1.7 voltage-gated sodium (NaV) channels stably expressed in mammalian HEK or CHO cells, respectively. Experiments with modified Cc1a peptides, truncated at the N-terminus (ΔG1–E5) or C-terminus (ΔW35–V39), demonstrated that the N- and C-termini are important for voltage-gated ion channel modulation. We conclude that Cc1a represents a novel pharmacological tool for probing the structure and function of L-type CaV channels.
Keyword Venom-peptide
Tarantula
Citharischius crawshayi
Peptide isomer
Voltage-gated calcium channel
Voltage-gated sodium channel
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
Centre for Advanced Imaging Publications
 
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Created: Thu, 10 Apr 2014, 10:45:17 EST by Susan Allen on behalf of Institute for Molecular Bioscience