AGAP, a new recombinant neurotoxic polypeptide, targets the voltage-gated calcium channels in rat small diameter DRG neurons

Liu, Xifang; Li, Chunli; Chen, Jian-Zhao; Du, Jingnan; Zhang, Jinghai; Li, Guixia; Jin, Xiaoquan; Wu, Chunfu

doi:10.1016/j.bbrc.2014.08.051

Cited by 12 publications

(7 citation statements)

References 35 publications

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“…Most of the long-chain scorpion peptides are the modulators of sodium and calcium channels (Possani et al, 2000; Li et al, 2004). The previous study has shown that AGAP potently inhibited voltage-gated calcium channels in the small diameter DRG neurons (Liu et al, 2014). We have demonstrated that AGAP decreases the HVA calcium channels, especially N-type calcium currents, while N-type calcium channels are expressed in presynaptic and may have more influence on EPSC/EPSP than other calcium type (Tsuzuki et al, 2004).…”

Section: Discussionmentioning

confidence: 97%

“…Our previous work has shown that AGAP potently inhibited voltage gated calcium channels (VGCCs), especially high-voltage activated calcium currents in rat DRG neurons (Liu et al, 2014). Here, we examined whether AGAP could attenuate pain behaviors in mice, and further assess the analgesic mechanisms of AGAP, the present study was therefore designed to evaluate the mechanisms of recombinant AGAP on the TTX-R sodium channels in rat small-diameter DRG neurons.…”

Section: Introductionmentioning

confidence: 99%

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Antinociceptive Effects of AGAP, a Recombinant Neurotoxic Polypeptide: Possible Involvement of the Tetrodotoxin-Resistant Sodium Channels in Small Dorsal Root Ganglia Neurons

Liu

et al. 2016

Front. Pharmacol.

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Antitumor-analgesic peptide (AGAP) is a novel recombinant polypeptide. The primary study showed that AGAP 1.0 mg/kg exhibited strong analgesic and antitumor effects. The tail vein administration of AGAP potently reduced pain behaviors in mice induced by intraplantar injection of formalin or intraperitoneal injection of acetic acid, without affecting basal pain perception. To further assess the mechanisms of AGAP, the effects of AGAP on sodium channels were assessed using the whole-cell patch clamp recordings in dorsal root ganglia (DRG) neurons. The results showed that AGAP (3–1000 nM) inhibited the sodium currents in small-diameter DRG neurons in a dose-dependent manner. 1000 nM AGAP could inhibit the current density-voltage relationship curve of sodium channels in a voltage-dependent manner and negatively shift the activation curves. 1000 nM AGAP could reduce the tetrodotoxin-resistant (TTX-R) sodium currents by 42.8% in small-diameter DRG neurons. Further analysis revealed that AGAP potently inhibited NaV1.8 currents by 59.4%, and negatively shifted the activation and inactivation kinetics. 1000 nM AGAP also reduced the NaV1.9 currents by 33.7%, but had no significant effect on activation and inactivation kinetics. Thus, our results demonstrated that submicromolar concentrations of AGAP inhibited TTX-R sodium channel in rat small-diameter DRG neurons. It is concluded that these new results may better explain, at least in part, the analgesic properties of this polypeptide.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Antinociceptive Effects of AGAP, a Recombinant Neurotoxic Polypeptide: Possible Involvement of the Tetrodotoxin-Resistant Sodium Channels in Small Dorsal Root Ganglia Neurons

Liu

et al. 2016

Front. Pharmacol.

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“…Moreover, scorpion toxins capable of controlling pain (i.e., analgesics) have been reported in the literature. Many of these analgesic toxins are not toxic to mammals, as they belong to a group of insect-specific neurotoxic α or β-toxins that interact with Na v , K v , and/or Ca v pathways [114,[184][185][186][187][188]. During the last two decades, over 20 scorpion venom-derived peptides and proteins have been reported to exert anti-nociceptive effects in vitro and in vivo.…”

Section: Analgesic Effectsmentioning

confidence: 99%

Scorpion Venom: Detriments and Benefits

et al. 2020

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Scorpion venom may cause severe medical complications and untimely death if injected into the human body. Neurotoxins are the main components of scorpion venom that are known to be responsible for the pathological manifestations of envenoming. Besides neurotoxins, a wide range of other bioactive molecules can be found in scorpion venoms. Advances in separation, characterization, and biotechnological approaches have enabled not only the development of more effective treatments against scorpion envenomings, but have also led to the discovery of several scorpion venom peptides with interesting therapeutic properties. Thus, scorpion venom may not only be a medical threat to human health, but could prove to be a valuable source of bioactive molecules that may serve as leads for the development of new therapies against current and emerging diseases. This review presents both the detrimental and beneficial properties of scorpion venom toxins and discusses the newest advances within the development of novel therapies against scorpion envenoming and the therapeutic perspectives for scorpion toxins in drug discovery.

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“…Liu et al indicated that AGAP potently blocked voltage-gated calcium channels (VGCCs), particularly high-voltage triggered calcium currents in rat DRG neurons [ 33 ]. Studies have shown that AGAP reduced HVA calcium channels, specifically N-type calcium currents, while N-type calcium channels are secreted at the presynaptic level and may have more effects on EPSC/EPSP than other calcium channel types [ 16 , 34 ].…”

Section: Bmk Agap and Voltage-gated Channelsmentioning

confidence: 99%

The Pivotal Potentials of Scorpion Buthus Martensii Karsch-Analgesic‐Antitumor Peptide in Pain Management and Cancer

Richard¹,

Kampo

Sackey

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Scorpion Buthus martensii Karsch -analgesic-antitumor peptide (BmK AGAP) has been used to treat diseases like tetanus, tuberculosis, apoplexy, epilepsy, spasm, migraine headaches, rheumatic pain, and cancer in China. AGAP is a distinctive long-chain scorpion toxin with a molecular mass of 7142 Da and composed of 66 amino acids cross-linked by four disulfide bridges. Voltage-gated sodium channels (VGSCs) are present in excitable membranes and partakes in essential roles in action potentials generation as compared to the significant function of voltage-gated calcium channels (VGCCs). A total of nine genes (Nav1.1–Nav1.9) have been recognized to encode practical sodium channel isoforms. Nav1.3, Nav1.7, Nav1.8, and Nav1.9 have been recognized as potential targets for analgesics. Nav1.8 and Nav1.9 are associated with nociception initiated by inflammation signals in the neuronal pain pathway, while Nav1.8 is fundamental for neuropathic pain at low temperatures. AGAP has a sturdy inhibitory influence on both viscera and soma pain. AGAP potentiates the effects of MAPK inhibitors on neuropathic as well as inflammation-associated pain. AGAP downregulates the secretion of phosphorylated p38, phosphorylated JNK, and phosphorylated ERK 1/2 in vitro. AGAP has an analgesic activity which may be an effective therapeutic agent for pain management because of its downregulation of PTX3 via NF-κB and Wnt/beta-catenin signaling pathway. In cancers like colon cancer, breast cancer, lymphoma, and glioma, rAGAP was capable of blocking the proliferation. Thus, AGAP is a promising therapy for these tumors. Nevertheless, research is needed with other tumors.

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AGAP, a new recombinant neurotoxic polypeptide, targets the voltage-gated calcium channels in rat small diameter DRG neurons

Cited by 12 publications

References 35 publications

Antinociceptive Effects of AGAP, a Recombinant Neurotoxic Polypeptide: Possible Involvement of the Tetrodotoxin-Resistant Sodium Channels in Small Dorsal Root Ganglia Neurons

Antinociceptive Effects of AGAP, a Recombinant Neurotoxic Polypeptide: Possible Involvement of the Tetrodotoxin-Resistant Sodium Channels in Small Dorsal Root Ganglia Neurons

Scorpion Venom: Detriments and Benefits

The Pivotal Potentials of Scorpion Buthus Martensii Karsch-Analgesic‐Antitumor Peptide in Pain Management and Cancer

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