α-Conotoxins Identify the α3β4* Subtype as the Predominant Nicotinic Acetylcholine Receptor Expressed in Human Adrenal Chromaffin Cells

Molecular Pharmacology
Arik J HoneAlmudena Albillos

Abstract

Ligands that selectively inhibit human α3β2 and α6β2 nicotinic acetylcholine receptor (nAChRs) and not the closely related α3β4 and α6β4 subtypes are lacking. Current α-conotoxins (α-Ctxs) that discriminate among these nAChR subtypes in rat fail to discriminate among the human receptor homologs. In this study, we describe the development of α-Ctx LvIA(N9R,V10A) that is 3000-fold more potent on oocyte-expressed human α3β2 than α3β4 and 165-fold more potent on human α6/α3β2β3 than α6/α3β4 nAChRs. This analog was used in conjuction with three other α-Ctx analogs and patch-clamp electrophysiology to characterize the nAChR subtypes expressed by human adrenal chromaffin cells. LvIA(N9R,V10A) showed little effect on the acetylcholine-evoked currents in these cells at concentrations expected to inhibit nAChRs with β2 ligand-binding sites. In contrast, the β4-selective α-Ctx BuIA(T5A,P6O) inhibited >98% of the acetylcholine-evoked current, indicating that most of the heteromeric receptors contained β4 ligand-binding sites. Additional studies using the α6-selective α-Ctx PeIA(A7V,S9H,V10A,N11R,E14A) indicated that the predominant heteromeric nAChR expressed by human adrenal chromaffin cells is the α3β4* subtype (asterisk indicates the po...Continue Reading

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Citations

Dec 19, 2016·European Journal of Pharmacology·Alicia Hernández-VivancoAlmudena Albillos
Oct 17, 2017·FEBS Letters·Arik J Hone, J Michael McIntosh
Sep 27, 2018·The Journal of Biological Chemistry·Arik J HoneJ Michael McIntosh
Oct 24, 2017·Pflügers Archiv : European journal of physiology·Almudena Albillos, J Michael McIntosh
Feb 22, 2021·Toxicon : Official Journal of the International Society on Toxinology·Yuanyuan QiangLei Wang
Oct 1, 2019·Tetrahedron Letters·Thilini D KondasingheJennifer L Stockdill
Sep 16, 2021·ACS Chemical Neuroscience·Yishuai YangSulan Luo

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