Abstract
Nicotinic acetylcholine receptor (nAChR), a member of pentameric ligand-gated ion channel transmembrane protein composed of five subunits, is widely distributed in the central and peripheral nervous system. The nAChRs are associated with various neurological diseases, including schizophrenia, Alzheimer’s disease, Parkinson’s disease, epilepsy and neuralgia. Receptors containing the α3 subunit are associated with analgesia, generating our interest in their role in pharmacological studies. In this study, α-conotoxin (α-CTx) LvIF was identified as a 16 amino acid peptide using a genomic DNA clone of Conus lividus (C. lividus). The mature LvIF with natural structure was synthesized by a two-step oxidation method. The blocking potency of α-CTx lvIF on nAChR was detected by a two-electrode voltage clamp. Our results showed that α-CTx LvIF was highly potent against rα3β2 and rα6/α3β2β3 nAChR subtypes, The half-maximal inhibitory concentration (IC50) values of α-CTx LvIF against rα3β2 and rα6/α3β2β3 nAChRs expressed in Xenopus oocytes were 8.9 nM and 14.4 nM, respectively. Furthermore, α-CTx LvIF exhibited no obvious inhibition on other nAChR subtypes. Meanwhile, we also conducted a competitive binding experiment between α-CTxs MII and LvIF, which showed that α-CTxs LvIF and MII bind with rα3β2 nAChR at the partial overlapping domain. These results indicate that the α-CTx LvIF has high potential as a new candidate tool for the studying of rα3β2 nAChR related neurophysiology and pharmacology.
Highlights
The Nicotinic acetylcholine receptor (nAChR), an important part of a cholinergic transmission of the central and peripheral nervous system and skeletal muscle neuromuscular junctions, is a classic nicotinesensitive ligand-gated ion channel of the cysteine-loop superfamily, which is endogenously activated by acetylcholine [1,2]
NAChR at the partial overlapping domain. These results indicate that the α-CTx LvIF has high potential as a new candidate tool for the studying of rα3β2 nAChR related neurophysiology and pharmacology
The nAChR, an important part of a cholinergic transmission of the central and peripheral nervous system and skeletal muscle neuromuscular junctions, is a classic nicotinesensitive ligand-gated ion channel of the cysteine-loop superfamily, which is endogenously activated by acetylcholine [1,2]
Summary
The nAChR, an important part of a cholinergic transmission of the central and peripheral nervous system and skeletal muscle neuromuscular junctions, is a classic nicotinesensitive ligand-gated ion channel of the cysteine-loop superfamily, which is endogenously activated by acetylcholine [1,2]. According to the distribution of nAChR in different tissues, it can be divided into muscular and neural nAChRs [3]. The neural nAChR is one of the most concerned ion channels and membrane proteins. The α3β2 nAChR is one of the important subtypes which is mainly distributed in the dorsal root ganglion and spinal cord [6]. Recent research shows that α3β2 nAChR is mainly related to pain and perception. The α3β2 nAChR located in the dorsal horn of the lumbar spinal cord and inhibited the release of glutamate from primary afferent C-fibers, subsequently reduced the sensitivity of rats to mechanical pain. Intrathecal injection of α3β2 nAChR antagonist decreased the pain threshold and enhanced the transmission of pain mechanical stimulation, accurate distribution and function of α3β2 nAChR still remains unknown [7]
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