Abstract：
:Pharmacologists have studied receptors for more than a century but a molecular understanding of their properties has emerged only during the past 30-35 years. In this article, I provide a personal retrospective of how developments and discoveries primarily during the 1970s and 1980s led to current concepts about the largest group of receptors, the superfamily of seven-transmembrane (7TM) receptors [also known as G-protein-coupled receptors (GPCRs)]. Significant technical advances such as the development of methods for radioligand binding, solubilization and purification of the beta(2)-adrenoceptor and other adrenoceptors led to the cloning of receptor genes and the discovery of their 7TM architecture and homology with rhodopsin. A universal mechanism of receptor regulation by G-protein-coupled receptor kinases (GRKs) and arrestins, originally discovered as a means of "desensitizing" G-protein-mediated second-messenger generation, was subsequently found to mediate both receptor endocytosis and activation of a growing list of signaling pathways such as those involving mitogen-activated protein kinases. Numerous opportunities for novel therapeutics should emerge from current and future research on 7TM receptor biology.
journal_name
Trends Pharmacol Scijournal_title
Trends in pharmacological sciencesauthors
Lefkowitz RJdoi
10.1016/j.tips.2004.06.006subject
Has Abstractpub_date
2004-08-01 00:00:00pages
413-22issue
8eissn
0165-6147issn
1873-3735pii
S0165-6147(04)00175-0journal_volume
25pub_type
历史文章,杂志文章abstract：:Three 'alpha 1-adrenoceptors' and three 'alpha 2-adrenoceptors' have now been cloned. How closely do these receptors match the native receptors that have been identified pharmacologically? What are the properties of these receptors, and how do they relate to other members of the cationic amine receptor family? Kevin L...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/0165-6147(91)90499-i
更新日期：1991-02-01 00:00:00
abstract：:Parkinson's disease (PD) is a progressive neurodegenerative disorder. Although therapies that treat the symptoms of the disease have proven efficacy, strategies that slow or stop the neurodegenerative process are currently not available. Recently, the National Institute of Neurological Disorders and Stroke (NINDS) con...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/j.tips.2004.03.003
更新日期：2004-05-01 00:00:00
abstract：:Five subtypes of muscarinic acetylcholine receptors have been identified in mammalian tissues, but the selectivity of ligands that are active at these receptors is low. It is possible, however, that selective compounds may be developed by targeting their allosteric site(s). Important new insights into the mechanism of...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/s0165-6147(00)89023-9
更新日期：1995-06-01 00:00:00
abstract：:Protein kinase Calpha (PKCalpha) is a member of the AGC (which includes PKD, PKG and PKC) family of serine/threonine protein kinases that is widely expressed in mammalian tissues. It is closely related in structure, function and regulation to other members of the protein kinase C family, but has specific functions wit...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
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更新日期：2010-01-01 00:00:00
abstract：:The pursuit for drugs that inhibit cyclin-dependent kinases (CDKs) has been an intense area of research for more than 15 years. The first-generation inhibitors, Flavopiridol and CY-202, are in late-stage clinical trials, but so far have demonstrated only modest activity. Several second-generation inhibitors are now in...
journal_title：Trends in pharmacological sciences
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doi：10.1016/j.tips.2007.10.012
更新日期：2008-01-01 00:00:00
abstract：:Zn(2+) is the second most prevalent trace element in the body and is present in particularly large concentrations in the mammalian brain. Although Zn(2+) is a cofactor for many enzymes in all tissues, a unique feature of brain Zn(2+) is its vesicular localization in presynaptic terminals, where its release is dependen...
journal_title：Trends in pharmacological sciences
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journal_title：Trends in pharmacological sciences
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更新日期：2018-09-01 00:00:00
abstract：:NMDA and non-NMDA (AMPA/kainate) antagonists have potential in the treatment of a diverse group of neurological disorders associated with excessive activation of excitatory amino acid receptors. Here Michael Rogawski reviews recent progress in the development of therapeutically useful NMDA receptor channel blockers an...
journal_title：Trends in pharmacological sciences
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abstract：:Classical targeted drug discovery is based on targeting druggable targets, typically kinases and receptors of which the function can be agonized or antagonized. This strategy meets difficulties in cases such as Huntington's disease (HD) and similar neurodegenerative disorders, where the pathological function of the pr...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/j.tips.2013.12.001
更新日期：2014-02-01 00:00:00
abstract：:Heat shock proteins (HSPs) constitute a large family of proteins involved in protein folding and maturation whose expression is induced by heat shock or other stressors. The major groups are classified based on their molecular weights and include HSP27, HSP40, HSP60, HSP70, HSP90, and large HSPs. HSPs play a significa...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/j.tips.2016.11.009
更新日期：2017-03-01 00:00:00
abstract：:The metabotropic glutamate type 7 (mglu(7)) receptor is a widely distributed, mainly presynaptic Group III mglu receptor that can regulate glutamate release. Recently, largely as a result of the identification of specific proteins that interact with the C-terminal domain of this receptor, considerable progress has bee...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/s0165-6147(00)01684-9
更新日期：2001-07-01 00:00:00
abstract：:Exposure of cells to agonists of receptors linked to G proteins can result in downregulation of cellular levels or redistribution of G proteins from membranes to the cytosol. Agonist-induced reductions in G protein levels have been observed for members of each of the Gs, Gi and Gq families of G proteins, are likely to...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/0165-6147(93)90064-Q
更新日期：1993-11-01 00:00:00
abstract：:cGMP inhibits hypertrophy, decreases fibrosis, and protects against cardiac ischemia-reperfusion (I/R) injury. Gene-targeting studies have not defined a clear role for its major downstream effector, cGMP-dependent protein kinase I (cGKI), in cardiac hypertrophy, but do implicate cGMP-cGKI signaling in fibrosis and I/R...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/j.tips.2014.05.003
更新日期：2014-08-01 00:00:00
abstract：:Receptors, enzymes, and ion channels are traditional targets of therapeutic development. A common strategy is to target these proteins with agents that either activate or suppress their activity with ligands or substrates that occupy orthosteric sites or have allosteric interactions. An alternative approach involves r...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/j.tips.2015.05.004
更新日期：2015-08-01 00:00:00
abstract：:N-Methyl-D-aspartate (NMDA) receptors are tetrameric ion channels containing two of four possible GluN2 subunits. These receptors have been implicated for decades in neurological diseases such as stroke, traumatic brain injury, dementia and schizophrenia. The GluN2 subunits substantially contribute to functional diver...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/j.tips.2011.08.003
更新日期：2011-12-01 00:00:00
abstract：:Gene therapy is a new field of medical research that has great potential to influence the course of treatment of human disease. The lung has been a particularly attractive target organ for gene therapy due to its accessibility and the identification of genetic deficits for a number of lung diseases. Several clinical t...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/s0165-6147(99)01350-4
更新日期：1999-06-01 00:00:00
abstract：:The GABAA receptor belongs, along with the nicotinic acetylcholine receptor, the glycine receptor and the 5-HT3 receptor, to a family of homologous transmitter-gated ion channels mediating fast synaptic transmission. Many classes of drug interact with the GABAA receptor, which is the major inhibitory ion channel in th...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/s0165-6147(97)01118-8
更新日期：1997-11-01 00:00:00
abstract：:Disorders of the central nervous system (CNS) have many etiologies compounded by limited options for treatment. The lack of successful treatments for these disorders stems from the difficulty of gaining effective access to the CNS through the blood-brain barrier, and the irreplaceable nature of neurons. Here, we revie...
journal_title：Trends in pharmacological sciences
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doi：10.1016/j.tips.2019.04.013
更新日期：2019-07-01 00:00:00
abstract：:Since G protein-coupled receptors (GPCRs) belong to a very large superfamily of evolutionarily related receptors (>800 members in humans), and due to the rapid progress on their structural biology, they are ideal candidates for polypharmacology studies. Broad screening and bioinformatics/chemoinformatics have been app...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章
doi：10.1016/j.tips.2014.10.009
更新日期：2014-12-01 00:00:00
abstract：:Neuromodulin is a neurospecific calmodulin binding protein that is implicated in neurite extension, axonal elongation and long-term potentiation. Yuechueng Liu and Daniel Storm propose that neuromodulin binds and concentrates calmodulin on growth cone membranes and that stimulation of protein kinase C releases high lo...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/0165-6147(90)90195-e
更新日期：1990-03-01 00:00:00
abstract：:Prospecting the full biodiversity of nature to find leads for new drugs is not necessary. Because finding leads is aimed at identifying biological activity, structure is of secondary importance. Furthermore, although natural chemical diversity might be unrivalled, functional diversity is bound to be considerably less....
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章
doi：10.1016/s0165-6147(02)02007-2
更新日期：2002-05-01 00:00:00
abstract：:Lithium is the simplest therapeutic agent available for the treatment of depression and has been used for over 100 years, yet no definitive mechanism for its effect has been established. Among the proposed mechanisms, two lithium-sensitive signal transduction pathways are active in the brain; these are mediated by gly...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章
doi：10.1016/s0165-6147(99)01428-5
更新日期：2000-02-01 00:00:00
abstract：:Daily rhythms in behavior, physiology, and metabolism are an integral part of homeostasis. These rhythms emerge from interactions between endogenous circadian clocks and ambient light-dark cycles, sleep-activity cycles, and eating-fasting cycles. Nearly the entire primate genome shows daily rhythms in expression in ti...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/j.tips.2018.07.003
更新日期：2018-09-01 00:00:00
abstract：:Drugs that cause liver injury often 'stress' mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and nuclear factor erythro...
journal_title：Trends in pharmacological sciences
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doi：10.1016/j.tips.2013.01.009
更新日期：2013-04-01 00:00:00
abstract：:Mechanisms of opioid tolerance have focused on adaptive modifications within cells containing opioid receptors, defined here as cellular allostasis, emphasizing regulation of the opioid receptor signalosome. We review additional regulatory and opponent processes involved in behavioral tolerance, and include mechanisti...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/j.tips.2016.08.002
更新日期：2016-11-01 00:00:00
abstract：:It is generally accepted that muscle wasting is caused by an increase in protein breakdown which seems to be associated with an ATP-dependent, non-lysosomal proteolytic system based on conjugation of proteins to the small polypeptide ubiquitin. Increases in ubiquitin conjugates and in ubiquitin mRNAs are found in the ...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/0165-6147(96)10021-3
更新日期：1996-06-01 00:00:00
abstract：:The ability to target specific cell types to achieve optimal distribution of therapeutic entities into diseased tissues, while limiting possible adverse off-target effects, has long been a goal of many research groups and pharmaceutical organizations. This review focuses on peptidic tissue-specific biomarkers that all...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/j.tips.2012.02.002
更新日期：2012-04-01 00:00:00
abstract：:The importance of the inhibitory neurotransmitter, GABA, within higher centres of the mammalian brain is unquestionable. However, its role within the spinal cord is of equal significance. There have been numerous studies over the past two decades that have established GABA as a neurotransmitter at both post- and presy...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/s0165-6147(96)01013-9
更新日期：1996-12-01 00:00:00
abstract：:5-Hydroxytryptamine (5-HT), dopamine and norepinephrine are important monoamine neurotransmitters implicated in multiple brain mechanisms and regulated by high-affinity transmembrane monoamine transporters. Although knockout mice lacking 5-HT, dopamine or norepinephrine transporters are widely used to assess brain mon...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
doi：10.1016/j.tips.2007.01.002
更新日期：2007-03-01 00:00:00
abstract：:Adenosine, when given by inhalation, initiates the narrowing of airways in subjects with asthma or chronic obstructive pulmonary disease (COPD). The underlying mechanism of this narrowing appears to involve the stimulation of specific mast cell surface adenosine receptors with the subsequent release of mediators and c...
journal_title：Trends in pharmacological sciences
pub_type： 杂志文章,评审
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更新日期：2003-08-01 00:00:00
