α_1-肾上腺素受体结构改变影响其生物学活性及生理功能的研究进展
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摘要
α_1-肾上腺素受体(α_1-ARs)属于G蛋白偶联受体,包含α_1A、α_1B、α_(1D)3种亚型。α_1-ARs结构改变可导致其生理功能的改变。该文总结了α_1-ARs羧基端截短、二聚化、别构效应和点突变的结构改变,导致其内吞、磷酸化、脱敏以及对激动剂的亲和力等生理功能的变化。
The α_1-adrenergic receptor( α_1-AR) belongs to Gprotein coupled receptors( GPCRs) and contains three subtypes,namely α_1 A,α_1 Band α_(1 D). Studies have shown that structural changes in the α_1-ARs receptor can lead to changes in their physiological functions. In the present study,we summarize the structural changes in four aspects of α_1-ARs receptors,including carboxy-terminal truncation,dimerization,allosteric effects,and point mutations that lead to endocytosis,phosphorylation,desensitization,and affinity for agonists.
The α_1-adrenergic receptor( α_1-AR) belongs to Gprotein coupled receptors( GPCRs) and contains three subtypes,namely α_1 A,α_1 Band α_(1 D). Studies have shown that structural changes in the α_1-ARs receptor can lead to changes in their physiological functions. In the present study,we summarize the structural changes in four aspects of α_1-ARs receptors,including carboxy-terminal truncation,dimerization,allosteric effects,and point mutations that lead to endocytosis,phosphorylation,desensitization,and affinity for agonists.
引文
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[24]Büscher R,Herrmann V,Ring K M,et al.Variability in phenylephrine response and essential hypertension:a search for human alpha(1B)-adrenergic receptor polymorphisms[J].J Pharmacol Exp T-her,1999,291(2):793-8.
[25]Nonen S,Okamoto H,Fujio Y,et al.Polymorphisms of norepinephrine transporter and adrenergic receptor alpha1D are associated with the response to beta-blockers in dilated cardiomyopathy[J].Pharmacogenomics J,2008,8(1):78-84.
[2]Rosenbaum D M,Cherezov V,Hanson M A,et al.GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function[J].Science,2007,318(5854):1266-73.
[3]Rasmussen S G,Choi H J,Rosenbaum D M,et al.Crystal structure of the human beta2 adrenergic G-protein-coupled receptor[J].Nature,2007,450(7168):383-7.
[4]Pupo A S,Minneman K P.Interaction of neuronal nitric oxide synthase with alpha1-adrenergic receptor subtypes in transfected HEK-293 cells[J].BMC Pharmacol,2002,2(17):1-7.
[5]Chen Z,Hague C,Hall R A,et al.Syntrophins regulate alpha1D-adrenergic receptors through a PDZ domain-mediated interaction[J].J Biol Chem,2006,281(18):12414-20.
[6]Lattion A L,Diviani D,Cotecchia S.Truncation of the receptor carboxyl terminus impairs agonist-dependent phosphorylation and desensitization of the alpha 1B-adrenergic receptor[J].J Biol Chem,1994,269(36):22887-93.
[5]Uberti M A,Hall R A,Minneman K P.Subtype-specific dimerization of alpha 1-adrenoceptors:effects on receptor expression and pharmacological properties[J].Mol Pharmacol,2003,64(6):1379-90.
[8]Gao X,Albee L J,Volkman B F,et al.Asymmetrical ligand-induced cross-regulation of chemokine(C-X-C motif)receptor 4 byα1-adrenergic receptors at the heteromeric receptor complex[J].Sci Rep,2018,8(1):2730-40.
[9]Albee L J,Eby J M,Tripathi A,et al.α1-adrenergic receptors function within hetero-oligomeric complexes with atypical chemokine receptor 3 and chemokine(C-X-C motif)receptor 4 in vascular smooth muscle cells[J].J Am Heart Assoc,2017,6(8):1-17.
[10]刘路路,陈京,白波.G蛋白偶联受体异源二聚体及其偏向性配体:未来药物研发的新主角[J].中国药理学通报,2013,29(10):1468-72.[10]Liu L L,Chen J,Bai B.GPCR heterodimer biased ligands:a crucial role in future drug discovery[J].Chin Pharmacol Bull,2013,29(10):1468-72.
[11]Copik A J,Ma C,Kosaka A,et al.Facilitatory interplay in alpha 1a and beta 2 adrenoceptor function reveals a non-Gq signaling mode:implications for diversification of intracellular signal transduction[J].Mol Pharmacol,2009,75(3):713-28.
[12]Uberti M A,Hague C,Oller H,et al.Heterodimerization with beta2-adrenergic receptors promotes surface expression and functional activity of alpha1D-adrenergic receptors[J].J Pharmacol Exp T-her,2005,313(1):16-23.
[13]Campbell A P,Wakelin L P,Denny W A,et al.Homobivalent conjugation increases the allosteric effect of 9-aminoacridine at theα1-adrenergic receptors[J].Mol Pharmacol,2017,91(2):135-44.
[14]Ciolek J,Ma6ga A,Marcon E,et al.Pharmacological characterization of zinc and copper interaction with the human alpha(1A)-adrenoceptor[J].Eur J Pharmacol,2011,655(1-3):1-8.
[15]Scheer A,Fanelli F,Diviani D,et al.Structure-function relationships of the alpha1b-adrenergic receptor[J].Eur Urol,1999,36(1):11-6.
[16]Kjelsberg M A,Cotecchia S,Ostrowski J,et al.Constitutive activation of the alpha 1B-adrenergic receptor by all amino acid substitutions at a single site.Evidence for a region which constrains receptor activation[J].J Biol Chem,1992,267(3):1430-3.
[17]Chen S,Xu M,Lin F,et al.Phe310 in transmembrane VI of the alpha1B-adrenergic receptor is a key switch residue involved in activation and catecholamine ring aromatic bonding[J].J Biol Chem,1999,274(23):16320-30.
[18]Scheer A,Fanelli F,Costa T,et al.Constitutively active mutants of the alpha 1B-adrenergic receptor:role of highly conserved polar amino acids in receptor activation[J].EMBO J,1996,15(14):3566-78.
[19]Hwa J,Graham R M,Perez D M.Chimeras of alpha1-adrenergic receptor subtypes identify critical residues that modulate active state isomerization[J].J Biol Chem,1996,271(14):7956-64.
[20]Freitas S R,Pereira A C,Floriano M S,et al.Association of alpha1a-adrenergic receptor polymorphism and blood pressure phenotypes in the Brazilian population[J].BMC Cardiovasc Disord,2008,8(40):1-7.
[21]Koshimizu T A,Yamauchi J,Hirasawa A,et al.Recent progress in alpha 1-adrenoceptor pharmacology[J].Biol Pharm Bull,2002,25(4):401-8.
[22]Shinoura H,Shibata K,Hirasawa A,et al.Key amino acids for differential coupling of alpha1-adrenergic receptor subtypes to Gs[J].Biochem Biophys Res Commun,2002,299(1):142-7.
[23]Ma6ga A,Merlin J,Marcon E,et al.Orthosteric binding ofρ-Da1a,a natural peptide of snake venom interacting selectively with theα1A-adrenoceptor[J].PLoS One,2013,8(7):1-11.
[24]Büscher R,Herrmann V,Ring K M,et al.Variability in phenylephrine response and essential hypertension:a search for human alpha(1B)-adrenergic receptor polymorphisms[J].J Pharmacol Exp T-her,1999,291(2):793-8.
[25]Nonen S,Okamoto H,Fujio Y,et al.Polymorphisms of norepinephrine transporter and adrenergic receptor alpha1D are associated with the response to beta-blockers in dilated cardiomyopathy[J].Pharmacogenomics J,2008,8(1):78-84.