Abstract：
:It is widely accepted that cAMP signaling is compartmentalized within cells. However, our knowledge of how receptors, cAMP signaling enzymes, effectors, and other key proteins form specific signaling complexes to regulate specific cell responses is limited. The multicomponent nature of these systems and the spatiotemporal dynamics involved as proteins interact and move within a cell make cAMP responses highly complex. Adenylyl cyclases, the enzymatic source of cAMP production, are key starting points for understanding cAMP compartments and defining the functional signaling complexes. Three basic elements are required to form a signaling compartment. First, a localized signal is generated by a G protein-coupled receptor paired to one or more of the nine different transmembrane adenylyl cyclase isoforms that generate the cAMP signal in the cytosol. The diffusion of cAMP is subsequently limited by several factors, including expression of any number of phosphodiesterases (of which there are 24 genes plus spice variants). Finally, signal response elements are differentially localized to respond to cAMP produced within each locale. A-kinase-anchoring proteins, of which there are 43 different isoforms, facilitate this by targeting protein kinase A to specific substrates. Thousands of potential combinations of these three elements are possible in any given cell type, making the characterization of cAMP signaling compartments daunting. This review will focus on what is known about how cells organize cAMP signaling components as well as identify the unknowns. We make an argument for adenylyl cyclases being central to the formation and maintenance of these signaling complexes.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Johnstone TB,Agarwal SR,Harvey RD,Ostrom RSdoi
10.1124/mol.117.110825subject
Has Abstractpub_date
2018-04-01 00:00:00pages
270-276issue
4eissn
0026-895Xissn
1521-0111pii
mol.117.110825journal_volume
93pub_type
杂志文章,评审abstract：:The verapamil-like arylazide (-)-[3H]azidopamil specifically photoaffinity labeled two low molecular mass polypeptides, with apparent molecular masses of 22 and 27 kDa, in the endoplasmic reticulum of guinea pig liver, kidney, adrenal gland, and lung. It was recently shown that the 22-kDa polypeptide binds the anti-is...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-11-01 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：:Guanine nucleotide-binding proteins (G proteins) transduce signals from agonist- and light-sensitive receptors. In the visual excitation system, the photon receptor rhodopsin is coupled to the G protein Gt (transducin). Gt is composed of alpha, beta, and gamma subunits; the alpha subunit binds guanine nucleotide, wher...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-06-01 00:00:00
abstract：:Binding of [3H](d)-N-allylnormetazocine ([3H](d)-NANM) to rat brain membranes is stereospecific, reversible, and saturable (Bmax = 260 fmol/mg of protein) and manifests moderately high affinity (Kd = 20 nM). The rank order of potency among opioidbenzomorphans and phencyclidine (PCP) analogs for competition for [3H](d)...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1985-01-01 00:00:00
abstract：:The effect of breast cancer resistance protein (Bcrp/Abcg2) on the disposition of the phytoestrogens daidzein, genistein, and coumestrol was investigated using Bcrp(-/-) mice. Expression of the genes for either mouse Bcrp or human BCRP in MDCK II cells induced apically directed transport of the three phytoestrogens, w...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.034751
更新日期：2007-10-01 00:00:00
abstract：:Atropine, the classic muscarinic receptor antagonist, inhibits ion currents mediated by neuronal nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes. At the holding potential of -80 mV, 1 microM atropine inhibits 1 mM acetylcholine-induced inward currents mediated by rat alpha2beta2, alpha2beta4, alp...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.52.5.886
更新日期：1997-11-01 00:00:00
abstract：:To screen for residues of hKv1.3 important for current block by the phenylalkylamine verapamil, the inactivated-state-reduced H399T mutant was used as a background for mutagenesis studies. This approach was applied mainly to abolish the accumulation in the inactivated blocked state, recovery from which in the wild typ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.012401
更新日期：2005-10-01 00:00:00
abstract：:The Gαi/o-coupled dopamine D2-like receptor family comprises three subtypes: the D2 receptor (D2R), with short and long isoform variants (D2SR and D2LR), D3 receptor (D3R), and D4 receptor (D4R), with several polymorphic variants. The common overlap of norepinephrine innervation and D2-like receptor expression pattern...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.115.101808
更新日期：2016-04-01 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：:To study the functional role of individual alpha1-adrenergic (AR) subtypes in blood pressure (BP) regulation, we used mice lacking the alpha1B-AR and/or alpha1D-AR with the same genetic background and further studied their hemodynamic and vasoconstrictive responses. Both the alpha1D-AR knockout and alpha1B-/alpha1D-AR...
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
abstract：:Current evidence suggests that DNA fragmentation plays an integral role in mediating cytotoxicity that results from thymidine nucleotide depletion ("thymineless death"). Recently, Ayusawa et al. [Mutat. Res. 200:221-230 (1988)] reported that dTMP starvation induces cellular processes that result in the release of 50-2...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-03-01 00:00:00
abstract：:Previous studies have demonstrated that the quinone group may play an important role in modulating the alkylating activity of quinone alkylating agents. Introduction of a quinone moiety markedly increased the alkylating activity and cytotoxic activity of the model quinone alkylating agents benzoquinone mustard and ben...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-09-01 00:00:00
abstract：:Stromal cell-derived factor-1 (SDF-1/CXCL-12) and vascular endothelial growth factor (VEGF), which can be secreted by hypoxic tumors, promote the generation of new blood vessels. These potent angiogenic factors stimulate endothelial cell migration via the activation of Rho GTPases and the phosphatidylinositol 3-kinase...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.109.060400
更新日期：2010-03-01 00:00:00
abstract：:The congenital long QT syndrome is an inherited disorder characterized by a delay in cardiac repolarization, leading to lethal cardiac arrhythmias such as torsade de pointes. One form of this disease involves mutations in the voltage-dependent cardiac Na(+) channel, which includes an in-frame deletion of three amino a...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：2000-02-01 00:00:00
abstract：:Undesired block of human ERG1 potassium channels is the basis for cardiac side effects of many different types of drugs. Therefore, it is important to know exactly why some drugs particularly bind to these channels with high affinity. Upon expression in mammalian cells and Xenopus laevis oocytes, we investigated the i...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.65.5.1120
更新日期：2004-05-01 00:00:00
abstract：:The role of the cGMP-dependent protein kinase (cGK) and one of its major substrates, the vasodilator-stimulated phosphoprotein (VASP), in the regulation of a receptor-evoked calcium response was investigated. The human type I beta cGK was stably transfected in human embryonic kidney 293 cells and Swiss mouse 3T6 fibro...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-08-01 00:00:00
abstract：:Retina from 1-day-old chicks is a valuable tissue model for studying neuronal nicotinic receptors because it expresses a large number of the developmentally regulated high affinity [(3)H]epibatidine labeled nicotinic receptors. Most of these receptors contain the beta4 subunit associated with different alpha subunits....
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.59.6.1410
更新日期：2001-06-01 00:00:00
abstract：:In this study, the expression of CYP26 is examined in relation to retinoid-induced mucosecretory differentiation in human tracheobronchial epithelial (HTBE) cells and compared with that in human lung carcinoma cell lines. In HTBE cells, retinoic acid (RA) inhibits squamous differentiation and induces mucous cell diffe...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.58.3.483
更新日期：2000-09-01 00:00:00
abstract：:Potassium channels play fundamental roles in physiology. Chemically diverse drugs bind in the pore region of K+ channels. Here, we homology-modeled voltage- and Ca2+-gated K+ channel BK and voltage-gated Kv1.3 using the X-ray structures of MthK and Kv1.2, respectively, and simulated the binding of d-tubocurarine in th...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.017970
更新日期：2006-04-01 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：:The ATP signaling mechanism in neuroblastoma x glioma hybrid NG108-15 cells differentiated by exposure to dibutyryl-cAMP was characterized. In cells loaded with fura-2, ATP rapidly raised the cytosolic Ca2+ concentration ([Ca2+]i); the magnitude of the rise was inversely proportional to the extracellular Na+ concentra...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-03-01 00:00:00
abstract：:The effect of ethanol on intracellular ionized calcium concentrations (Cai) was studied in synaptosomes isolated from mouse whole brain and in hepatocytes isolated from rat liver. The fluorescent calcium chelator, fura-2, was used to quantitate Cai. Incubation of synaptosomes with ethanol (350-700 mM) increased restin...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-12-01 00:00:00
abstract：:The interaction of quinidine with a cloned human cardiac potassium channel (HK2) expressed in a stable mouse L cell line was studied using the whole-cell tight-seal voltage-clamp technique. Quinidine (20 microM) did not affect the initial sigmoidal activation time course of the current. However, it reduced the peak cu...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1992-02-01 00:00:00
abstract：:Immune-mediated drug hypersensitivity reactions (IDHRs) represent a significant problem due to their unpredictable and severe nature, as well as the lack of understanding of the pathogenesis. Sulfamethoxazole (SMX), a widely used antibiotic, has been used as a model compound to investigate the underlying mechanism of ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.043273
更新日期：2008-06-01 00:00:00
abstract：:Small-molecule restoration of wild-type structure and function to mutant p53 (so-called mutant reactivation) is a highly sought-after goal in cancer drug development. We previously discovered that small-molecule zinc chelators called zinc metallochaperones (ZMCs) reactivate mutant p53 by restoring zinc binding to zinc...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.116.107409
更新日期：2017-06-01 00:00:00
abstract：:Capacitative Ca2+ influx, which occurs in response to mobilization of intracellular Ca2+ stores, is a general feature of many cell types. Although the mechanism of capacitative Ca2+ entry is not known, evidence suggests the involvement of small G proteins that are prenylated on a cysteine residue near their carboxyl t...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-12-01 00:00:00
abstract：:Human serum butyrylcholinesterase (Hu BChE) is a promising therapeutic against the toxicity of chemical warfare nerve agents. We have showed previously that recombinant (r) Hu BChE can be expressed at very high levels, 400 to 600 U/ml in mouse blood, by delivering the Hu BChE gene using adenovirus (Ad). Here, we repor...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.109.055665
更新日期：2009-09-01 00:00:00
abstract：:Tritiated dextromethorphan ([3H]DM) binds to two distinct sites in guinea pig brain, a high-affinity site (Kd = 13-20 nM) and a low-affinity site (Kd greater than 200 nM). Binding of [3H] DM to the high-affinity site is rapid, reversible, saturable, proportional to tissue concentration, and pH-dependent. The sites hav...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-05-01 00:00:00
abstract：:Membrane trafficking of the δ-opioid receptor (DOR) from intracellular compartments to plasma membrane in central neurons, induced by various pathological conditions such as long-term opioid exposure, represents unique receptor plasticity involved in the mechanisms of long-term opioid effects in opioid addiction and o...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.111.076307
更新日期：2012-03-01 00:00:00
abstract：:The response of myeloid leukemia cells to treatment with 1-beta-D-arabinofuranosylcytosine (ara-C) includes activation of the c-Abl protein tyrosine kinase and the stress-activated protein kinase (SAPK). The present studies demonstrate that treatment of human U-937 leukemia cells with ara-C is associated with transloc...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.61.6.1489
更新日期：2002-06-01 00:00:00
