title: RegIIA: an α4/7-conotoxin from the venom of Conus regius that potently blocks α3β4 nAChRs.
abstract: Neuronal nicotinic acetylcholine receptors (nAChRs) play pivotal roles in the central and peripheral nervous systems. They are implicated in disease states such as Parkinson's disease and schizophrenia, as well as addictive processes for nicotine and other drugs of abuse. Modulation of specific nAChRs is essential to understand their role in the CNS. α-Conotoxins, disulfide-constrained peptides isolated from the venom of cone snails, potently inhibit nAChRs. Their selectivity varies markedly depending upon the specific nAChR subtype/α-conotoxin pair under consideration. Thus, α-conotoxins are excellent probes to evaluate the functional roles of nAChRs subtypes. We isolated an α4/7-conotoxin (RegIIA) from the venom of Conus regius. Its sequence was determined by Edman degradation and confirmed by sequencing the cDNA of the protein precursor. RegIIA was synthesized using solid phase methods and native and synthetic RegIIA were functionally tested using two-electrode voltage clamp recording on nAChRs expressed in Xenopus laevis oocytes. RegIIA is among the most potent antagonist of the α3β4 nAChRs found to date and is also active at α3β2 and α7 nAChRs. The 3D structure of RegIIA reveals the typical folding of most α4/7-conotoxins. Thus, while structurally related to other α4/7 conotoxins, RegIIA has an exquisite balance of shape, charge, and polarity exposed in its structure to potently block the α3β4 nAChRs.
authors: Department of Chemistry & Biochemistry, Florida Atlantic University, 777 Glades Rd., Boca Raton, FL 33431, USA.
authors: Aldo
authors: A
authors: Franco
authors: Shiva N
authors: SN
authors: Kompella
authors: Kalyana B
authors: KB
authors: Akondi
authors: Christian
authors: C
authors: Melaun
authors: Norelle L
authors: NL
authors: Daly
authors: Charles W
authors: CW
authors: Luetje
authors: Paul F
authors: PF
authors: Alewood
authors: David J
authors: DJ
authors: Craik
authors: David J
authors: DJ
authors: Adams
authors: Frank
authors: F
authors: Marí
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020916:Conotoxins / Q000302:isolation & purification / Q000494:pharmacology*; D052078:Conus Snail; D008969:Molecular Sequence Data; D008978:Mollusk Venoms / Q000302:isolation & purification / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000302:isolation & purification / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000302:isolation & purification / Q000378:metabolism* / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D020916:Conotoxins; D008978:Mollusk Venoms; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C569968:alpha4 nicotinic acetylcholine receptor, Conus regius; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403530:nicotinic receptor alpha3beta4