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Distinct regulation of sigma‐1 receptor multimerization by its agonists and antagonists
Author(s) -
Hong W. Conrad
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.665.11
Subject(s) - chemistry , dimer , tetramer , mutant , ligand (biochemistry) , receptor , sigma 1 receptor , stereochemistry , receptor–ligand kinetics , biophysics , microbiology and biotechnology , biochemistry , agonist , biology , gene , organic chemistry , enzyme
Since its initial proposal four decades ago, extensive studies have shown that the sigma‐1 receptor (σ 1 R) interacts with and modulates the activity of multiple proteins with important functions. Recent crystal structures of σ 1 R as a homo‐trimer differ from a dimer‐tetramer model postulated by early work. Further it is not clear whether ligand binding regulates σ 1 R multimerization. Here I conducted mutational analyses and examined ligands' effects on σ 1 R oligomerization using novel non‐denaturing gels. In transfected cells σ 1 R exhibited as monomer, dimer, and mainly as high‐order multimers. Agonists ((+)pentazocine, (+)SKF10,047, DTG, PRE‐084) decreased, whereas antagonists (BD1008, BD1047, BD1063, haloperidol, NE‐100, progesterone) increased σ 1 R multimers, suggesting that agonists and antagonists differentially affect the stability of σ 1 R multimers. Mutations at key residues lining the trimerization interface abolished multimerization but preserved dimerization. Intriguingly, deletion of the transmembrane domain (TM) reduced σ 1 R to monomer. These results demonstrate that multiple domains play crucial roles in coordinating high‐order quaternary organization of σ 1 R, which may comprise interconvertible oligomeric states in a dynamic equilibrium. σ 1 R multimers exhibited high‐affinity and high‐capacity [ 3 H](+)pentazocine binding, whereas monomers lacked binding. In competition binding the antagonist haloperidol appeared to show an apparent 10‐fold higher potency in wild‐type σ 1 R than in mutants with only dimers, which might explain why haloperidol binding increased σ 1 R multimers. Further, a σ 1 R mutant (E102Q) implicated in early‐onset amyotrophic lateral sclerosis exhibited as dimer only, suggesting that dysregulation of σ 1 R quaternary structure impairs its physiological function. Further exploration of ligand‐regulated σ 1 R multimerization may provide novel approaches to modulate the function of σ 1 R and its interacting proteins. Support or Funding Information Butler University Faculty Startup Fund This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .