Function of ACV 1 As A Highly Selective Antagonist

2018-10-10

Introduction 

Conotoxins are small peptides of 12 to 19 amino acids, which act as highly selective antagonists of ion channels in animal cells. A subgroup of these, the 4, 7 loop class of α-conotoxins Vc1.1 (ACV 1), interacts selectively with neuronal-type nAChRs and the degree of selectivity for different nAChR subtypes is remarkable. The coding sequence of ACV 1 consists of 201 base pairs, which translates into 66 amino acids. The predicted pre-region of the protein precursor has 21 amino acids, the pro-region has 29 amino acids, and the mature peptide is 16 amino acids in length. The peptide ACV 1, as synthesized by solid-phase techniques, had 16 amino acids with a C-terminal amide and with two disulfide bonds connected in a 4, 7 loop structure, whose mass was confirmed by ESI-MS as 1806.6. The characteristics of ACV 1 are those of a specific antagonist of neuronal nAChRs.

Pharmacologic action

ACV 1 is a highly specific competitive inhibitor of neuronal nAChR responses in vitro, so the most likely mechanism for the analgesic effect of ACV 1 is by blocking peripheral neuronal nAChRs. Although a central effect cannot be excluded, no evidence is available to date to support such a proposition. ACV 1 blocks the calcigenic nAChRs and then blocks the opening of voltage-operated calcium channels. Blocking of such nAChRs by ACV 1 could lead to a reduction in sodium and calcium influx and a reduction in sensitization of the voltage-operated calcium channels and ectopic discharge from sensory neurons. Such a mechanism could explain the suppression of hyperalgesia by ACV 1.

Function

ACV 1 can specifically antagonize neuronal but not muscle-type nAChRs. This conotoxin was also shown to suppress the vascular response to selective stimulation of sensory nerves in rats, suggesting that antagonists of nAChRs had the potential to suppress pain transmission in these animals. The analgesic effect of strong nicotinic agonists, such as epibatidine, nicotine and analogues has been well documented and supports the involvement of nicotinic transmission in pain perception. There is, however, no precedent for the use of nicotinic antagonists to suppress pain transmission in animals in vivo. Neuropathic pain presents a continuing management problem as current treatments are in the main ineffective or not well tolerated. ACV 1 is a neuronal-type nicotinic receptor antagonist and an effective and long-lasting analgesic in two rat models (CCI and PNL) of human neuropathic pain.

Pharmacokinetics and metabolism

ACV 1 peptide was soluble in water and stable in solution when tested after 8 weeks. ACV 1 was shown in bovine and rat assay systems in vitro and in vivo, respectively, to inhibit in vitro a neuronal nicotinic acetylcholine receptor response and to inhibit in vivo a vascular response to pain.

References:

Satkunanathan N, Livett B, Gayler K, et al. Alpha-conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurons [J]. Brain Research, 2005, 1059(2):149-158.

Dutton J L, Craik D J. alpha-Conotoxins: nicotinic acetylcholine receptor antagonists as pharmacological tools and potential drug leads. [J]. Current Medicinal Chemistry, 2001, 8(4): 327 - 344.

Sandall D W, Satkunanathan N, Keays D A,et al. A Novel α-Conotoxin Identified by Gene Sequencing Is Active in Suppressing the Vascular Response to Selective Stimulation of Sensory Nerves in Vivo † [J]. Biochemistry, 2003, 42(22):6904.

Mcintosh J M, And A D S, Olivera B M. Conus Peptides Targeted to Specific Nicotinic Acetylcholine Receptor Subtypes. Annual Review of Biochemistry, 68(1):59[J].

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