A novel alpha conotoxin (α-PIB) isolated from C. purpurascens is selective for skeletal muscle nicotinic acetylcholine receptors

The α-conotoxin family is comprised of peptides that share the following arrangement of cysteine residues in the primary amino acid sequence: –CC–C–C–, where each dash represents a variable number of amino acids. The number of amino acids between cysteine residues has been used to group the α-conotoxins into distinct subfamilies. These subfamilies include the α4/7-, α4/3- and α3/5-conotoxins, so named for the number of amino acids between 2nd/3rd and 3rd/4th cysteine residues, respectively. The α3/5-conotoxins antagonize vertebrate-muscle nicotinic acetylcholine receptors (nAChRs), while the α4/7- and α4/3-conotoxins primarily inhibit vertebrate neuronal nAChRs. To date, these three subfamilies are the most extensively characterized of the α-conotoxin family. Here we report the purification and characterization of an unusual α4/4-conotoxin, α-conotoxin PIB (α-PIB), from the venom of Conus purpurascens, with the following amino-acid sequence: ZSOGCCWNPACVKNRC (Z=pyroglutamate, O=hydroxyproline). This peptide demonstrates high affinity inhibition of vertebrate-muscle nAChRs, and paralytic effects when injected in vivo. Testing of α-PIB against other receptors indicated that the inhibitory effect is specific for skeletal muscle nAChRs. α-PIB shares the key biochemical and pharmacological characteristics of the α-conotoxin family.