AA sequence: RDPCCSNPVCTVHNPQIC-NH2
Disulfide bonds: Cys4-Cys10 and Cys5-Cys18
Formula: C79H125N27O25S4
Molecular Weight: 1981.29 g/mol
Appearance: White lyophilized solid
Solubility: water or saline buffer
Source: Synthetic
Purity rate: > 95 %
α-Conotoxin PIA
α-conotoxin PIA has been isolated from the venom of the marine snail Conus purpurascens. α-conotoxin PIA preferentially targets neuronal AChR subtypes containing α6 subunits. The peptide displays 75-fold higher affinity for rat α6/α3β2β3 nAChRs over rat α3β2 nAChRs. α-conotoxin PIA potently inhibits human chimeric α6/α3β2β3 nAChRs (IC50 of 1.7 nM) and provided similar results on rat chimeric α6/α3β2β3 (IC50 of 0.95 nM). 10 μM α-conotoxin PIA has no effect on the adult form of the human muscle nAChR demonstrating a high specificity for α6-containing neuronal nAChRs. The peptide has no effect on α2- and α4-containing neuronal nAChRs. α6-containing neuronal nAChRs are highly expressed in several catecholaminergic nuclei (locus coeruleus, ventral tegmental area and substantia nigra), play a significant role in nicotinic reward and dependence, and is a therapeutic target of interest in Parkinson disease.
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Conotoxin PIA Is Selective for α6 Subunit-Containing Nicotinic Acetylcholine Receptors
Dowell C., et al. (2003) -Conotoxin PIA Is Selective for α6 Subunit-Containing Nicotinic Acetylcholine Receptors
Until now, there have been no antagonists to discriminate between heteromeric nicotinic acetylcholine receptors (nAChRs) containing the very closely related α6 and α3 subunits. nAChRs containing α3, α4, or α6 subunits in combination with β2, occasionally β4, and sometimes β3 or α5 subunits, are thought to play important roles in cognitive function, pain perception, and the reinforcing properties of nicotine. We cloned a novel gene from the predatory marine snail Conus purpurascens. The predicted peptide, α-conotoxin PIA, potently blocks the chimeric α6/α3β2β3 subunit combination as expressed in oocytes but neither the muscle nor the major neuronal nAChR α4β2. Additionally, this toxin is the first described ligand to discriminate between nAChRs containing α6 and α3 subunits. Exploiting the unusual intron conservation of conotoxin genes may represent a more general approach for defining conotoxin ligand scaffolds to discriminate among closely related receptor populations.
Mysterious α6-containing nAChRs: function, pharmacology, and pathophysiology
Yang KC., et al. (2009) Mysterious α6-containing nAChRs: function, pharmacology, and pathophysiology
Neuronal nicotinic acetylcholine receptors (nAChRs) are the superfamily of ligand-gated ion channels and widely expressed throughout the central and peripheral nervous systems. nAChRs play crucial roles in modulating a wide range of higher cognitive functions by mediating presynaptic, postsynaptic, and extrasynaptic signaling. Thus far, nine alpha (α2-α10) and three beta (β2, β3, and β4) subunits have been identified in the CNS, and these subunits assemble to form a diversity of functional nAChRs. Although α4β2- and α7-nAChRs are the two major functional nAChR types in the CNS, α6*-nAChRs are abundantly expressed in the midbrain dopaminergic (DAergic) system, including mesocorticolimbic and nigrostriatal pathways, and particularly present in presynaptic nerve terminals. Recently, functional and pharmacological profiles of α6*-nAChRs have been assessed with the use of α6 subunit blockers such as α-conotoxin MII and PIA, and also by using α6 subunit knockout mice. By modulating DA release in the nucleus accumbens (NAc) and modulating GABA release onto DAergic neurons in the ventral tegmental area (VTA), α6*-nAChRs may play important roles in the mediation of nicotine reward and addiction. Furthermore, α6*-nAChRs in the nigrostriatal DAergic system may be promising targets for selective preventative treatment of Parkinson’s disease (PD). Thus, α6*-nAChRs may hold promise for future clinical treatment of human disorders, such as nicotine addiction and PD. In this review, we mainly focus on the recent advances in the understanding of α6*-nAChR function, pharmacology and pathophysiology.