Abstract:
:Bovine adrenal zona fasciculata (AZF) cells express a noninactivating K+ current (IAC) that sets the resting membrane potential and may mediate depolarization-dependent cortisol secretion. External ATP stimulates cortisol secretion through activation of a nucleotide receptor. In whole-cell patch clamp recordings from bovine AZF cells, we found that ATP selectively inhibited IAC K+ current by a maximum of 75.7 +/- 3% (n = 13) with a 50% inhibitory concentration of 1.3 microM. A rapidly inactivating A-type K+ current was not inhibited by ATP. Other nucleotides, including ADP and the pyrimidines UTP and UDP, also inhibited IAC, whereas 2-methylthio-ATP (2-MeSATP) and CTP were completely ineffective. The rank order of potency for six nucleotides was UTP = ADP > ATP > UDP > 2-MeSATP = CTP. At maximally effective concentrations, UTP, ADP, and UDP inhibited IAC current by 81.4 +/- 5.2% (n = 7), 70.7 +/- 7.2% (n = 4), and 65.2 +/- 7.9% (n = 5), respectively. Inhibition of IAC by external ATP was reduced from 71. 3 +/- 3.2% to 22.8 +/- 4.5% (n = 18) by substituting guanosine 5'-O-2-(thio) diphosphate for GTP in the patch pipette. Inhibition of IAC by external ATP (10 microM) was markedly suppressed (to 17.3 +/- 5.5%, n = 9) by the nonspecific protein kinase antagonist staurosporine (1 microM) and eliminated by substituting the nonhydrolyzable ATP analog 5-adenylyl-imidodiphosphate or UTP for ATP in the pipette. ATP-mediated inhibition of IAC was not altered by the kinase C antagonist calphostin C, the calmodulin inhibitory peptide, or by buffering the intracellular (pipette) Ca++ with 20 mM 1,2-bis-(2-aminophenoxy)ethane-N, N,N',N'-tetraacetic acid. In current clamp recordings, ATP and UTP (but not CTP) depolarized AZF cells at concentrations that inhibited IAC K+ current. These results demonstrate that bovine AZF cells express a nucleotide receptor with a P2Y3 agonist profile that is coupled to the inhibition of IAC K+ channels through a GTP-binding protein. The inhibition of IAC K+ current and associated membrane depolarization are the first cellular responses demonstrated to be mediated through this receptor. Nucleotide inhibition of IAC proceeds through a pathway that is independent of phospholipase C, but that requires ATP hydrolysis. The identification of a new signaling pathway in AZF cells, whereby activation of a nucleotide receptor is coupled to membrane depolarization through inhibition of a specific K+ channel, suggests a mechanism for ATP-stimulated corticosteroid secretion that depends on depolarization-dependent Ca++ entry. This may be a means of synchronizing the stress-induced secretion of corticosteroids and catecholamines from the adrenal gland.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Xu L,Enyeart JJdoi
10.1124/mol.55.2.364subject
Has Abstractpub_date
1999-02-01 00:00:00pages
364-76issue
2eissn
0026-895Xissn
1521-0111journal_volume
55pub_type
杂志文章abstract::The dopamine D3 receptor, although structurally similar to the dopamine D2 receptor, has 100-fold higher affinity for agonists such as dopamine and quinpirole, when these receptors are expressed in 293 cells. Additionally, the D3 receptor has generally lower affinity for several antagonists than does the D2 receptor. ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-08-01 00:00:00
abstract::Magnesium modulates hormone-sensitive adenylate cyclase activation. In the present studies, we have examined the magnesium requirement of beta-adrenergic-stimulated adenylate cyclase activity in permeabilized human lymphocytes. Following isoproterenol pretreatment, under conditions that lead to homologous beta-adrener...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-03-01 00:00:00
abstract::The ligand-binding sites of many G protein-coupled receptors (GPCRs) are situated around and deeply embedded within the central pocket formed by their seven transmembrane-spanning α-helical domains. Generally, these binding sites are assumed accessible to endogenous ligands from the aqueous phase. Recent advances in t...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.118.115113
更新日期:2019-11-01 00:00:00
abstract::All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. atRA is also used as a drug, and synthetic atRA analogs and inhibitors of retinoic acid (RA) metabolism have been developed. The hepatic clearance of atRA is mediated primarily by CYP26A1, but design of CYP26A1 inhibitors is hindered by lack of info...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.072413
更新日期:2011-08-01 00:00:00
abstract::Using an oligonucleotide based on the sequence of a porcine brain muscarinic receptor cDNA, we recently cloned four distinct muscarinic receptors from the rat and human genomes. In the present study we transfected the rat homolog of the porcine brain muscarinic receptor cDNA into A9 L cells using a mammalian expressio...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-10-01 00:00:00
abstract::A polyamine component of Agelenopsis aperta spider venom designated FTX is reported to be a selective antagonist of P-type calcium channels in the mammalian brain. Consequently, this component has frequently been used as a pharmacological tool to determine the presence, distribution, and function of P-type channels in...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-10-01 00:00:00
abstract::Of four monoclonal antibodies to purified rat liver cytochrome P450s, including those from 3-methylcholanthrene-, phenobarbital-, ethanol-, and pregnenolone-16-alpha-carbonitrile-treated rats, only the monoclonal antibody against pregnenolone-16-alpha-carbonitrile-inducible P450 immunodetected proteins in chicken live...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-05-01 00:00:00
abstract::The binding affinities of 16 7-substituted 2,3-dichlorodibenzo-p-dioxins for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cytosolic receptor protein from male Wistar rats have been determined. The EC50 value for each compound was estimated by competitive displacement of [3H]TCDD and the data illustrated that the dif...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-06-01 00:00:00
abstract::Pancreatic cancer is one of the most lethal types of tumors with no effective therapy available; is currently the third leading cause of cancer in developed countries; and is predicted to become the second deadliest cancer in the United States by 2030. Due to the marginal benefits of current standard chemotherapy, the...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.118.115444
更新日期:2019-07-01 00:00:00
abstract::The lymphocyte potassium channel Kv1.3 is widely regarded as a promising new target for immunosuppression. To identify a potent small-molecule Kv1.3 blocker, we synthesized a series of 5-phenylalkoxypsoralens and tested them by whole-cell patch clamp. The most potent compound of this series, 5-(4-phenylbutoxy)psoralen...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.6.1364
更新日期:2004-06-01 00:00:00
abstract::When expressed via an inducible promoter in human embryonic kidney 293 cells, the rat Mas-related gene D (rMrgD) receptor responded to beta-alanine but not L-alanine by elevating intracellular [Ca(2+)], stimulating phosphorylation of the mitogenactivated protein kinases known as extracellular signal-regulated kinase (...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.018788
更新日期:2006-02-01 00:00:00
abstract::Two human ovarian cancer cell lines were established from a patient before (PEO1) and after (PEO4) the onset of resistance to 5-fluorouracil (5-FU)/cisplatin-based chemotherapy. Using growth inhibition assays, we determined that the PEO4 line was almost 5-fold more resistant to 5-FU than the PEO1 line. The addition of...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-09-01 00:00:00
abstract::Dynamin is a GTPase enzyme involved in membrane constriction and fission during endocytosis. Phospholipid binding via its pleckstrin homology domain maximally stimulates dynamin activity. We developed a series of surface-active small-molecule inhibitors, such as myristyl trimethyl ammonium bromide (MiTMAB) and octadec...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.034207
更新日期:2007-12-01 00:00:00
abstract::Cytokines are thought to cause the depression of cytochrome P-450 (CYP)-associated drug metabolism in humans during inflammation and infection. We have examined the role of five cytokines, i.e., interleukin-1 beta, interleukin-4, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, on the expression of CY...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-10-01 00:00:00
abstract::Studies investigating the effects of beta-naphthoflavone (beta NF) on insulin receptor binding and its intrinsic protein kinase activity in rat liver and placenta were performed. Membranes were prepared from maternal liver and placenta on gestation day 11 and used for [125I]insulin radioreceptor assay. Scatchard analy...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-03-01 00:00:00
abstract::We previously described the development of genetic models to study the in vivo functions of the hepatic cytochrome P450 (P450) system, through the hepatic deletion of either cytochrome P450 oxidoreductase [POR; HRN (hepatic reductase null) line] or cytochrome b(5) [HBN (hepatic cytochrome b(5) null) line]. However, HR...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.084616
更新日期:2013-06-01 00:00:00
abstract::It has long been believed that the cortical actin cytoskeleton plays an important role in regulating the secretion of hormones and neurotransmitters. In this study, we investigated the control of actin dynamics in primary neuroendocrine cells and determined the relationship of actin dynamics to various components of t...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.008474
更新日期:2005-04-01 00:00:00
abstract::Previous studies have established that two Xbal polymorphic restriction fragments [11.5 and 44 kilobases (kb)] hydridizing to a full length debrisoquin hydroxylase cDNA are associated with two different mutant alleles for the debrisoquin hydroxylase gene (IID6). An independent allele, defined by Xbal 16- and 9-kb frag...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-05-01 00:00:00
abstract::The putative serotonin (5-HT) agonist RU 24969 [5-methoxy-3-1,2,3,6-tetrahydropyridin-4-yl)indole; 5-MeO-THPI] has been extensively used in the study and classification of 5-HT receptors. In order to study molecular determinants for recognition of THPIs at central 5-HT recognition sites, about 25 additional THPI deriv...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-07-01 00:00:00
abstract::The present study investigates mRNA and protein levels of A3 adenosine receptors in resting (R) and activated (A) human lymphocytes. The receptors were evaluated by the antagonist radioligand [3H]5-N-(4-methoxyphenyl-carbamoyl)amino-8-propyl-2(2furyl)-pyrazolo-[4,3e]-1,2,4-triazolo-[1,5-c]-pyrimidine ([3H]MRE 3008F20)...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.3.711
更新日期:2004-03-01 00:00:00
abstract::15-Deoxy delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), an activator of peroxisome proliferator-activated receptor (PPAR)-gamma and -delta, is a prostanoid metabolite with anti-inflammatory actions. In intrauterine tissues, proinflammatory cytokines and prostaglandins have been identified as playing key roles in the ma...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.009449
更新日期:2005-07-01 00:00:00
abstract::We have identified four new mu-opiod receptor (MOR)-1 exons, indicating that the gene now contains at least nine exons spanning more than 200 kilobases. Replacement of exon 4 by combinations of the new exons yields three new receptors. When expressed in Chinese hamster ovary cells, all three variants displayed high af...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.56.2.396
更新日期:1999-08-01 00:00:00
abstract::The regulation of the cellular distribution and intracellular signaling properties of the alpha(1B)- and alpha(1D)- adrenoceptor (alpha(1)-AR) subtypes was examined in stably transfected Rat 1 fibroblasts. In unstimulated cells, alpha(1B)-AR expression was noted primarily on the cell surface. Treatment with phenylephr...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.57.4.659
更新日期:2000-04-01 00:00:00
abstract::In previous studies, it was shown that the overexpression of beta2-adrenoceptor (beta2AR) in the hearts of transgenic mice (Tg) leads to agonist-independent activation of adenylate cyclase and enhanced myocardial function. Here, we measured the physical coupling of beta2AR and Gs by evaluating the coimmunoprecipitatio...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.52.2.187
更新日期:1997-08-01 00:00:00
abstract::We have studied the mechanism of action of Arg(*)-Arg-Nal(2)-Cys(1x)-Tyr-Gln-Lys-(d-Pro)-Pro-Tyr-Arg-Cit-Cys(1x)-Arg-Gly-(d-Pro)(*) (POL3026), a novel specific beta-hairpin mimetic CXC chemokine receptor (CXCR)4 antagonist. POL3026 specifically blocked the binding of anti-CXCR4 monoclonal antibody 12G5 and the intrace...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.042911
更新日期:2008-04-01 00:00:00
abstract::In the last years, reactive oxygen species (ROS) have been proposed as mediators of proliferative/hypertrophic responses to angiotensin II (Ang II), both in vivo and in vitro. However, the hypothesis that the Ang II-dependent cell contraction could be mediated by ROS, particularly H2O2, has not been tested. Present ex...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.1.104
更新日期:2001-01-01 00:00:00
abstract::Caveolins have been recognized over the past few decades as key regulators of cell physiology. They are ubiquitously expressed and regulate a number of processes that ultimately impact efficiency of cellular processes. Though not critical to life, they are central to stress adaptation in a number of organs. The follow...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.117.111237
更新日期:2018-04-01 00:00:00
abstract::G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABAB receptor (GABABR) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABABR has been ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.107854
更新日期:2017-09-01 00:00:00
abstract::By limiting unrestricted activation of intracellular effectors, compartmentalised signalling of cyclic nucleotides confers specificity to extracellular stimuli and is critical for the development and health of cells and organisms. Dissecting the molecular mechanisms that allow local control of cyclic nucleotide signal...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.119.118869
更新日期:2020-02-28 00:00:00
abstract::The midbrain periaqueductal gray (PAG) is involved in organizing behavioral responses to threat, stress, and pain. These PAG functions are modulated by cholinergic agents. In the present study, we examined the cholinergic modulation of synaptic transmission in the PAG using whole-cell voltage-clamp recordings from rat...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.045872
更新日期:2008-11-01 00:00:00