Abstract:
:Organic anion transporter-1 (OAT1) mediates the body disposition of a diverse array of clinically important drugs, including anti-HIV therapeutics, antitumor drugs, antibiotics, antihypertensives, and anti-inflammatories. Therefore, understanding the regulation of OAT1 has profound clinical significance. We previously established that OAT1 constitutively internalizes from and recycles back to cell surface and that activation of protein kinase C (PKC) inhibits OAT1 activity by promoting ubiquitination of the transporter, which then leads to an accelerated internalization of the transporter from cell surface to intracellular compartments. In the current study, we showed that PKC isoform PKCα was responsible for OAT1 ubiquitination. To directly address the role of OAT1 ubiquitination, we then generated two OAT1 mutants, each having multiple lysines (K) simultaneously mutated to arginine (R). One mutant K163/297/303/315/321R lost sensitivities to PKC-induced inhibition of transport activity, to PKC-induced ubiquitination, and to PKC-induced acceleration of transporter internalization. Further dissecting each lysine in this mutant, we identified Lys297, Lys303, and Lys315 as being the ubiquitin conjugation sites. Of interest, mutating any one of the three lysines prevented the ubiquitin conjugation to the other two lysines, suggesting that Lys297, Lys303, and Lys315 may form an optimal structure to interact with ubiquitination machineries. This is the first demonstration that Lys297, Lys303, and Lys315 play a synergistic role in PKC-regulated OAT1 ubiquitination, trafficking, and transport activity.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Li S,Zhang Q,You Gdoi
10.1124/mol.113.086769subject
Has Abstractpub_date
2013-07-01 00:00:00pages
139-46issue
1eissn
0026-895Xissn
1521-0111pii
mol.113.086769journal_volume
84pub_type
杂志文章abstract::Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin. In the present study, we investigated the role of the tPA-plasmin system in depolarization-evoked dopamine (DA) and acetylcholine (ACh) release in the nucleus accumbens (NAc) and hippocampus, respectively, of mic...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.022467
更新日期:2006-11-01 00:00:00
abstract::Hypertriglyceridemia is a frequent complication accompanying the treatment of patients with either retinoids or rexinoids, [retinoid X receptor (RXR)-selective retinoids]. To investigate the cellular and molecular basis for this observation, we have studied the effects of rexinoids on triglyceride metabolism in both n...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.2.170
更新日期:2001-02-01 00:00:00
abstract::Valproic acid (VPA) is a widely used antiepileptic agent that is undergoing clinical evaluation for anticancer therapy. We assessed the effects of VPA on angiogenesis in vitro and in vivo. In human umbilical vein endothelial cells, therapeutically relevant concentrations of VPA (0.25 to 1 mM) inhibited proliferation, ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.3.520
更新日期:2004-03-01 00:00:00
abstract::The fluorogenic sulfhydryl probe 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin (CPM) (1-50 nM) is used to characterize the functional role and location of highly reactive thiol groups on the ryanodine-sensitive Ca2+ release channel complex [i.e., ryanodine receptors (RyRs)] of skeletal and cardiac junctional...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-02-01 00:00:00
abstract::The human dopamine and norepinephrine transporters (hDAT and hNET, respectively) control neurotransmitter levels within the synaptic cleft and are the site of action for amphetamine (AMPH) and cocaine. We investigated the role of a threonine residue within the highly conserved and putative phosphorylation sequence RET...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.069039
更新日期:2011-03-01 00:00:00
abstract::The binding of agonists and antagonists to alpha 2-adrenergic receptors of human platelets was studied. The receptors showed homogeneous affinities for antagonists but two affinity states for the agonist (-)-epinephrine, which were modulated by guanine nucleotides. Van't Hoff plots of antagonist binding had a break po...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-03-01 00:00:00
abstract::We describe the nucleic acid sequence encoding a human 5-hydroxytryptamine1D (5-HT1D) serotonin receptor and some of the functional characteristics of the gene product. The receptor gene was isolated by hybridization to a probe based on a canine thyroid cDNA (called RDC4) previously isolated by others and believed to ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-08-01 00:00:00
abstract::β-Adrenergic receptor blockers (β-blockers) are commonly used to treat heart failure, but the biologic mechanisms governing their efficacy are still poorly understood. The complexity of β-adrenergic signaling coupled with the influence of receptor polymorphisms makes it difficult to intuit the effect of β-blockers on ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.090951
更新日期:2014-08-01 00:00:00
abstract::Thiourea, phenylthiourea, and methimazole perfused into rat liver stimulated the biliary efflux of GSSG without affecting the excretion of GSH into either the bile or the caval perfusate. The thiocarbamide moiety appears essential, since perfusion with urea, phenylurea, or N-methylimidazole did not stimulate GSSG rele...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-07-01 00:00:00
abstract::Although the thiopurine drugs 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are well established agents for the treatment of leukemia, controversies remain regarding their main mode of action. Previous evidence has suggested that although 6-TG exerts a cytotoxic effect through incorporation of 6-thioguanine nucleot...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.62.1.102
更新日期:2002-07-01 00:00:00
abstract::Reconstitution experiments with purified components reproduce the basic characteristics of receptor/G protein coupling, i.e., GTP-sensitive high affinity agonist binding and receptor-promoted GTP binding. However, the interaction of agonists with the A1 adenosine receptor in rat and bovine but not human brain membrane...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-11-01 00:00:00
abstract::Many progestins have been developed for use in contraception, menopausal hormone therapy, and treatment of gynecological diseases. They are derived from either progesterone or testosterone, and they act by binding to the progesterone receptor (PR), a hormone-inducible transcription factor belonging to the nuclear rece...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.054312
更新日期:2009-06-01 00:00:00
abstract::Sazetidine-A has been recently proposed to be a "silent desensitizer" of alpha4beta2 nicotinic acetylcholine receptors (nAChRs), implying that it desensitizes alpha4beta2 nAChRs without first activating them. This unusual pharmacological property of sazetidine-A makes it, potentially, an excellent research tool to dis...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.045104
更新日期:2008-06-01 00:00:00
abstract::CYP3A4 is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60% of clinically used drugs. Many drugs are able to induce the expression of CYP3A4, which usually causes drug-drug interactions and adverse drug reactions. This study aims to explore the role of histone modificatio...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.117.108225
更新日期:2017-08-01 00:00:00
abstract::Neuroactive steroids have been postulated to cause anesthesia by binding to unique steroid recognition sites on gamma-aminobutyric acid (GABA) receptors and modulating GABA receptor function. Steroids interact with these sites diastereoselectively, but it is unknown whether steroid sites show enantioselectivity. To ad...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-12-01 00:00:00
abstract::The NO/cGMP signaling pathway plays a major role in the cardiovascular system, in which it is involved in the regulation of smooth muscle tone and inhibition of platelet aggregation. Under pathophysiological conditions such as endothelial dysfunction, coronary artery disease, and airway hyperreactivity, smooth muscle ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.020909
更新日期:2006-06-01 00:00:00
abstract::Two peptides, which have no significant homology with known protein structures, were obtained by microsequencing of a mu-opioid binding protein purified to homogeneity from bovine striatal membranes. Polyclonal antibodies generated against portions of these peptides immunoprecipitated up to 65% of radiolabeled purifie...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-10-01 00:00:00
abstract::The gamma-aminobutyric acid(A) (GABA(A)) receptor contains a binding site (or sites) for benzodiazepines and related ligands. Previous studies have shown that the residue occupying position 101 (rat numbering) of the alpha subunit is particularly important in determining how some of these compounds interact with the r...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1999-10-01 00:00:00
abstract::To identify novel factors or mechanisms that are important for the resistance of tissues to chemical toxicity, we have determined the mechanisms underlying the previously observed increases in resistance to acetaminophen (APAP) toxicity in the lateral nasal gland (LNG) of the male Cyp2g1-null/Cyp2a5-low mouse. Initial...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.070045
更新日期:2011-04-01 00:00:00
abstract::Hepatic very-low-density lipoprotein particles (VLDL) containing full-length apolipoprotein B100 are metabolized in the blood stream to low-density lipoprotein (LDL) particles, whose elevated levels increase the risk of atherosclerosis. Statins and bile-acid sequestrants are effective LDL-lowering therapies for many p...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.2.269
更新日期:2002-02-01 00:00:00
abstract::To determine the relationship between vascular alpha 1-adrenergic receptor occupancy and receptor-coupled calcium flux, we have studied [3H]prazosin binding and l-norepinephrine-induced 45Ca efflux in cultured vascular smooth muscle cells isolated from the rabbit aorta. In a crude cellular homogenate, [3H]prazosin bou...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-05-01 00:00:00
abstract::Molecular cloning of the alpha 2A-adrenergic receptor has shown that this receptor is a member of the gene superfamily of guanine nucleotide-binding protein (G protein)-coupled receptors. The alpha 2A-adrenergic receptor expressed in Chinese hamster ovary (CHO) cells attenuates and potentiates forskolin-stimulated cAM...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-08-01 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::Cyclic nucleotide analogs were used to study relaxation of pig coronary arteries and guinea pig tracheal smooth muscle in an attempt to determine the roles of cAMP- and cGMP-dependent protein kinases (cA-K and cG-K). In pig coronary artery strips, cGMP analogs were generally more effective than cAMP analogs in promoti...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-10-01 00:00:00
abstract::Previous studies have shown that exposure of phenobarbital-pretreated rats to halothane in 10% O2 causes centrilobular necrosis, induces expression of the 72-kDa heat shock protein (HSP72), and produces several trifluoroacetylated adducts. In the present study the time course of development of the centrilobular lesion...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-10-01 00:00:00
abstract::The cDNA for the rat alpha 1c-adrenergic receptor (AR) has been cloned using a probe derived from the bovine alpha 1c-AR sequence. Clone rB7a has a 2.6-kilobase insert with a 1390-base pair open reading frame and encodes a receptor of 466 amino acids. The cloned receptor has 91% amino acid identity with the bovine alp...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-09-01 00:00:00
abstract::Receptors for the serine protease thrombin and for lysophospholipids are coupled to G proteins and control a wide range of cellular functions, including mitogenesis. Activators of these receptors are present in blood, and can enter the brain during central nervous system (CNS) injury. Reactive astrogliosis, a prominen...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.5.1199
更新日期:2003-11-01 00:00:00
abstract::Many cellular signaling pathways share regulation by protein phosphatase-2A (PP2A), a widely expressed serine/threonine phosphatase, and the heterotrimeric G protein Galpha(12). PP2A activity is altered in carcinogenesis and in some neurodegenerative diseases. We have identified binding of Galpha(12) with the Aalpha s...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.033555
更新日期:2007-05-01 00:00:00
abstract::Ro 11-2465 is a cyanide derivative of imipramine. In cerebral cortex homogenates, [3H] Ro 11-2465 displays a binding profile similar to that of [3H]imipramine. Agents compete with binding of [3H]Ro 11-2465 in an order of potency similar to their ability to block serotonin uptake, and raphe lesions greatly decrease the...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1983-05-01 00:00:00
abstract::It has been demonstrated previously that cannabinol (CBN) differentially modulates interleukin-2 (IL-2) protein secretion by T cells with a corresponding change in extracellular signal-regulated kinase activity. The objective of the present studies was to further investigate the molecular mechanism by which CBN enhanc...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.2.446
更新日期:2002-02-01 00:00:00