Abstract：
:Although G protein-coupled receptors are often categorized in terms of their primary coupling to a given type of Gα protein subunit, it is now well established that many show promiscuous coupling and activate multiple signaling pathways. Furthermore, some agonists selectively activate signaling pathways by promoting interaction between distinct receptor conformational states and particular Gα subunits or alternative signaling proteins. We have tested the capacity of agonists to stimulate Ca(2+) release, cAMP accumulation, and changes in extracellular acidification rate (ECAR) at the human α(1A)-adrenoceptor. Signaling bias factors were determined by novel application of an operational model of agonism and compared with the reference endogenous agonist norepinephrine; values significantly different from 1.0 indicated an agonist that promoted receptor conformations distinct from that favored by norepinephrine. Oxymetazoline was a full agonist for ECAR and a partial agonist for Ca(2+) release (bias factor 8.2) but failed to stimulate cAMP production. Phenylephrine showed substantial bias toward ECAR versus Ca(2+) release or cAMP accumulation (bias factors 21 and 33, respectively) but did not display bias between Ca(2+) and cAMP pathways. Cirazoline and N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide (A61603) displayed bias toward cAMP relative to Ca(2+) release (bias factors of 7.4 and 8.6). It is noteworthy that epinephrine, a second endogenous adrenoceptor agonist, did not display bias relative to norepinephrine. Our finding that phenylephrine displayed significant signaling bias, despite being highly similar in structure to epinephrine, indicates that subtle differences in agonist-receptor interaction can affect conformational changes in cytoplasmic domains and thereby modulate the repertoire of effector proteins that are activated.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Evans BA,Broxton N,Merlin J,Sato M,Hutchinson DS,Christopoulos A,Summers RJdoi
10.1124/mol.110.067454subject
Has Abstractpub_date
2011-02-01 00:00:00pages
298-307issue
2eissn
0026-895Xissn
1521-0111pii
mol.110.067454journal_volume
79pub_type
杂志文章abstract：:We investigated the mechanisms of MDR1 gene activation by CCAAT/enhancer binding protein beta (C/EBPbeta, or nuclear factor for interleukin 6) in human cancer cells. Transfection of the breast cancer cell line MCF-7 and its doxorubicin-selected variant MCF-7/ADR by either C/EBPbeta or C/EBPbeta-LIP (a dominant-negativ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.65.4.906
更新日期：2004-04-01 00:00:00
abstract：:A quantum chemical study of adenosine, formycin, and their 2-NH2 and 2-F derivatives is performed. The tautomerism of neutral and protonated species as well as the protonation of adenosine, formycin, and their derivatives are theoretically studied using semiempirical MNDO and AM1, as well as ab initio STO-3G methods. ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1989-02-01 00:00:00
abstract：:Cytosolic sulfotransferase 1C3 (SULT1C3) is the least characterized of the three human SULT1C subfamily members. Originally identified as an orphan SULT by computational analysis of the human genome, we recently reported that SULT1C3 is expressed in human intestine and LS180 colorectal adenocarcinoma cells and is upre...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.116.106005
更新日期：2016-11-01 00:00:00
abstract：:Pregnanolone [5 beta-pregnan-3 alpha-ol-20-one (5 beta 3 alpha)] and allopregnanolone [5 alpha-pregnan-3 alpha-ol-20-one (5 alpha 3 alpha)] are neuroactive steroids that are reduced metabolites of progesterone. Both 5 beta 3 alpha and 5 alpha 3 alpha are potent positive modulators of the gamma-aminobutyric acid respon...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-07-01 00:00:00
abstract：:We investigated the interactions of the anticancer drug vinorelbine with drug efflux transporters and cytochrome P450 3A drug-metabolizing enzymes. Vinorelbine was transported by human multidrug-resistance associated protein (MRP) 2, and Mrp2 knockout mice displayed increased vinorelbine plasma exposure after oral adm...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.111.077099
更新日期：2012-10-01 00:00:00
abstract：:The MUC1 C-terminal transmembrane subunit (MUC1-C) oncoprotein is a direct activator of the canonical nuclear factor-kappaB (NF-kappaB) RelA/p65 pathway and is aberrantly expressed in human multiple myeloma cells. However, it is not known whether multiple myeloma cells are sensitive to the disruption of MUC1-C functio...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.110.065011
更新日期：2010-08-01 00:00:00
abstract：:GABAA receptors are modulated by a variety of compounds, including the neurosteroids and barbiturates. Although the effects of barbiturates on alphabetagamma isoforms, thought to dominate phasic (synaptic) GABAergic inhibition, have been extensively studied, the effects of pentobarbital on kinetic properties of alphab...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.002543
更新日期：2004-10-01 00:00:00
abstract：:Functional coupling between muscarinic (m3) receptors and two voltage-gated K+ (Kv) channels (Kv1.2 and Kv1.5) cloned originally from canine colonic smooth muscle was studied using the Xenopus oocytes expression system and a mammalian cell line (COS cells). Oocytes were coinjected with cRNAs encoding the human m3 rece...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-12-01 00:00:00
abstract：:The observations from Dunlap and Fischbach that transmitter-mediated shortening of the duration of action potentials could be caused by a decrease in calcium conductance led to numerous studies of the mechanisms of modulation of voltage-dependent calcium channels. Calcium channels are well known targets for inhibition...
journal_title：Molecular pharmacology
pub_type： 杂志文章,评审
doi：10.1124/mol.104.002261
更新日期：2004-11-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-06-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.61.5.1124
更新日期：2002-05-01 00:00:00
abstract：:Iron-loading diseases remain an important problem because of the toxicity of iron-catalyzed redox reactions. Iron loading occurs in the mitochondria of Friedreich's ataxia (FA) patients and may play a role in its pathogenesis. This suggests that iron chelation therapy could be useful. We developed previously the lipop...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.108.046847
更新日期：2008-07-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.017756
更新日期：2006-03-01 00:00:00
abstract：:Histone deacetylase inhibitors (HDACi), which have emerged as a new class of anticancer agents, act by modulating expression of genes controlling apoptosis or cell proliferation. Here, we compared the effect of HDACi on transcriptional activation by estrogen or glucocorticoid receptors (ER and GR, respectively), two m...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.014514
更新日期：2005-12-01 00:00:00
abstract：:Microglia, as phagocytes and antigen-presenting cells in the central nervous system, are activated in such disease processes as stroke and multiple sclerosis. Because peripheral macrophages are capable of producing endocannabinoids, we have examined endocannabinoid production in a macrophage-colony stimulating factor ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.65.4.999
更新日期：2004-04-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-05-01 00:00:00
abstract：:The interaction of hormones acting via the mobilization of calcium and stimulation of cAMP levels in cells was examined by determining the effects of carbachol and forskolin on cAMP and cGMP accumulation in mouse parotid gland. Treatment of isolated acini with either carbachol (0.01 to 20 microM) or forskolin (1 micro...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-10-01 00:00:00
abstract：:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was found to activate protein kinases under cell- and nucleus-free conditions in isolated C57 mouse liver cytosol (100,000 x g supernatant). This action of TCDD was found to be aryl hydrocarbon receptor (AHR) dependent, concentration dependent, and inhibited by genistein, a t...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.52.4.667
更新日期：1997-10-01 00:00:00
abstract：:Iron is a biologically essential metal, but excess iron can cause damage to the cardiovascular and nervous systems. We examined the effects of extracellular Fe²⁺ on permeation and gating of Ca(V)3.1 channels stably transfected in HEK293 cells, by using whole-cell recording. Precautions were taken to maintain iron in t...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.112.080184
更新日期：2012-12-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.007500
更新日期：2005-03-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-07-01 00:00:00
abstract：:Norcocaine nitroxide and N-hydroxynorcocaine were found to stimulate hepatic microsomal lipid peroxidation in vitro, as measured by spin-trapping techniques using the spin trap alpha-[4-pyridyl-1-oxide]-N-tert-butylnitrone. It was determined that either norcocaine nitroxide or N-hydroxynorcocaine markedly enhanced the...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1982-11-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 评论,杂志文章,评审
doi：10.1124/mol.105.020727
更新日期：2006-02-01 00:00:00
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journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-11-01 00:00:00
abstract：:An investigation of the conformational profiles of two cyclic delta-selective opioid peptides, [D-Pen2,D-Pen5]-enkephalin and [D-Pen2,L-Pen5]-enkephalin, has been made. The methods and procedures used are more extensive and systematic than those previously reported, involving a combination of nested grid rotations, cy...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-04-01 00:00:00
abstract：:Reversible binding of warfarin to defatted serum albumin was studied by equilibrium dialysis at pH 7.4, in a 66 mM sodium phosphate buffer at 37 degrees. The binding isotherm could be described by two stoichiometric binding constants, K1 in the range 141,000 to 192,000 M-1 and K2 at 39,000 to 57,000 M-1. At least two ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1985-02-01 00:00:00
abstract：:The gamma-aminobutyric acid-A (GABA(A)) receptor complex is allosterically modulated by a variety of substances, some of clinical importance. Barbiturates and neurosteroids augment GABA-currents and also directly gate the channel. A variety of gamma-butyrolactone analogues also modulate GABA-induced currents, with som...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.52.1.114
更新日期：1997-07-01 00:00:00
abstract：:The cannabinoid analog abnormal cannabidiol [abn-cbd; (-)-4-(3-3,4-trans-p-menthadien-[1,8]-yl)-olivetol] does not bind to CB(1) or CB(2) receptors, yet it acts as a full agonist in relaxing rat isolated mesenteric artery segments. Vasorelaxation by abn-cbd is endothelium-dependent, pertussis toxin-sensitive, and is i...
journal_title：Molecular pharmacology
pub_type： 评论,杂志文章
doi：10.1124/mol.63.3.699
更新日期：2003-03-01 00:00:00
abstract：:Opioid analgesics are used extensively in the management of pain. Although the clinically effective opioids bind with high affinity to the mu-opioid receptor, studies have suggested that the delta-opioid agonists might represent more ideal analgesic agents, with fewer side effects. A limitation to opiate effectiveness...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.52.2.272
更新日期：1997-08-01 00:00:00
abstract：:Both in vivo and in vitro treatments with the irreversible protein-modifying reagent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), were used to investigate rat striatal D1 dopamine receptor/effector interactions. Peripherally administered EEDQ markedly reduced D1 dopamine receptor binding and D1 dopamine rec...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-01-01 00:00:00
