Huwentoxin-XVI, an analgesic, highly reversible mammalian N-type calcium channel antagonist from Chinese tarantula Ornithoctonus huwena.
N-type calcium channels play important roles in the control of neurotransmission release and transmission of pain signals to the central nervous system. Their selective inhibitors are believed to be potential drugs for treating chronic pain. In this study, a novel neurotoxin named Huwentoxin-XVI (HWTX-XVI) specific for N-type calcium channels was purified and characterized from the venom of Chinese tarantula Ornithoctonus huwena. HWTX-XVI is composed of 39 amino acid residues including six cysteines that constitute three disulfide bridges. HWTX-XVI could almost completely block the twitch response of rat vas deferens to low-frequency electrical stimulation. Electrophysiological assay indicated that HWTX-XVI specifically inhibited N-type calcium channels in rat dorsal root ganglion cells (IC50 ∼60 nM). The inhibitory effect of HWTX-XVI on N-type calcium channel currents was dose-dependent and similar to that of CTx-GVIA and CTx-MVIIA. However, the three peptides exhibited markedly different degrees of reversibility after block. The toxin had no effect on voltage-gated T-type calcium channels, potassium channels or sodium channels. Intraperitoneal injection of the toxin HWTX-XVI to rats elicited significant analgesic responses to formalin-induced inflammation pain. Toxin treatment also changed withdrawal latency in hot plate tests. Intriguingly, we found that intramuscular injection of the toxin reduced mechanical allodynia induced by incisional injury in Von Frey test. Thus, our findings suggest that the analgesic potency of HWTX-XVI and its greater reversibility could contribute to the design of a novel potential analgesic agent with high potency and low side effects.
Department of Biochemistry, School of Life Sciences, Central South University, Changsha, Hunan 410013, China; Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China. Electronic address: dengmch@csu.edu.cn.
Meichun
M
Deng
Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.
Xuan
X
Luo
Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.
Yucheng
Y
Xiao
Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.
Zhenghua
Z
Sun
Department of Parasitology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China.
Liping
L
Jiang
Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.
Zhonghua
Z
Liu
Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China.
Xiongzhi
X
Zeng
Department of Biochemistry, School of Life Sciences, Central South University, Changsha, Hunan 410013, China.
Hanchun
H
Chen
Department of Biochemistry, School of Life Sciences, Central South University, Changsha, Hunan 410013, China.
Jianhua
J
Tang
Department of Biochemistry, School of Life Sciences, Central South University, Changsha, Hunan 410013, China.
Weimin
W
Zeng
Key Laboratory of Protein Chemistry and Developmental Biology of the Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China. Electronic address: liangsp@hunnu.edu.cn.
Songping Liang
D000595:Amino Acid Sequence; D000700:Analgesics / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000188:drug therapy*; D008297:Male; D008969:Molecular Sequence Data; D010146:Pain / Q000188:drug therapy*; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism; D013111:Spider Venoms / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D013112:Spiders; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology; D014982:Xenopus laevis
D000700:Analgesics; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020747:Calcium Channels, T-Type; D015221:Potassium Channels; D015222:Sodium Channels; D013111:Spider Venoms; C000593235:huwentoxin-XVI, Ornithoctonus huwena
Analgesic action; Dorsal root ganglia; HWTX-XVI; N-type calcium channels; Pain model; Rat vas deferens; Tarantula toxin