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Transactions of the Association of... 1990
Review
Topics: Amino Acid Sequence; Animals; Cloning, Molecular; DNA; Humans; Male; Molecular Sequence Data; RNA, Messenger; Rabbits; Rats; Receptors, Adrenergic, alpha; Tissue Distribution
PubMed: 1966743
DOI: No ID Found -
Molecular Pharmacology Sep 1984The structure of the alpha 1-adrenergic receptor was investigated by comparing polypeptides identified by sodium dodecyl sulfate (NaDodSO4)-polyacrylamide gel...
The structure of the alpha 1-adrenergic receptor was investigated by comparing polypeptides identified by sodium dodecyl sulfate (NaDodSO4)-polyacrylamide gel electrophoresis with the size of the intact receptor in cell membranes as determined by target size analysis. The alpha 1-adrenergic receptor from rat liver membranes affinity-labeled with [3H]phenoxybenzamine, a covalent affinity reagent, appeared as a single polypeptide with a molecular mass of 85,000 daltons (Da) on NaDodSO4-polyacrylamide gels. In the absence of protease inhibitors, smaller peptides of 58-62 kDa and 40-45 kDa, specifically labeled with [3H]phenoxybenzamine, were also apparent on NaDodSO4 gels. In order to determine whether the 85-kDa protein represented all or only a portion of the alpha 1-receptor, radiation inactivation (target size analysis) was undertaken. Radiation-induced receptor inactivation was measured by the loss of specific [3H]phenoxybenzamine and [3H]prazosin binding and by the loss of affinity-labeled alpha 1-adrenergic receptors on NaDodSO4 gels. Target size analysis of rat liver alpha 1-receptors indicated that the intact membrane-bound receptor has an average molecular mass of 160,000 Da. These data suggest that the intact alpha-receptor may exist in the membrane as a dimer of two 85,000-Da subunits. The structure of the alpha 1-receptor was further studied by limited proteolysis of the 85-kDa protein isolated from NaDodSO4 gels. Trypsin, chymotrypsin, and papain produce smaller peptides similar to those produced during membrane isolation in the absence of protease inhibition. Limited proteolysis of the membrane-bound receptor produces water-soluble peptides, the largest of which is 45,000 Da. This peptide contains the ligand-binding domain and protrudes from the membrane into the extracellular space.
Topics: Animals; Binding, Competitive; Cell Membrane; Electrophoresis, Polyacrylamide Gel; Endopeptidases; Kinetics; Liver; Molecular Weight; Peptide Fragments; Phenoxybenzamine; Rats; Receptors, Adrenergic, alpha; Solubility
PubMed: 6090881
DOI: No ID Found -
Progress in Clinical and Biological... 1980
Review
Topics: Animals; Antibodies; Binding Sites; Cardiovascular Diseases; Heart; Lung; Molecular Conformation; Receptors, Adrenergic; Receptors, Adrenergic, beta; Respiratory Tract Diseases
PubMed: 6248889
DOI: No ID Found -
Archives of Medical Research 1999The beta 3 subtype of adrenaline and noradrenaline receptors has been extensively characterized at structural and functional levels. Ligand binding and adenyl cyclase... (Review)
Review
The beta 3 subtype of adrenaline and noradrenaline receptors has been extensively characterized at structural and functional levels. Ligand binding and adenyl cyclase activation studies have helped to define their unique beta-adrenergic profile. Humans, other larger mammals, and rodents share most of the characteristic beta 3-adrenergic receptor properties, although obvious species-specific differences have been identified. Most studies in animal models have shown a distinct beta 3-adrenergic receptor activity that results in an increase in energy expenditure, decrease of fat mass (especially of intra-abdominal fat), and increased glucose disposal efficiency. It is of interest that mild weight increase was shown to develop in female but not male mice, in whom the beta 3-adrenergic receptor gene was disrupted. Recently, the incidence of a naturally occurring variant of the human beta 3-adrenergic receptor was shown to correlate with hereditary obesity in Pima Indians and Japanese individuals. In Western obese patients, this phenotype increased the capacity to gain weight and develop type 2 diabetes mellitus. Studies of humans with the Trp64Arg variant have shown controversial results. Many studies have failed to show any effect in heterozygous male subjects, and only modest effects in homozygous male subjects. In women, several studies have shown modest-to-significant effects regarding weight gain, intra-abdominal fat, and decreased insulin sensitivity in heterozygous and homozygous women. Other studies have failed to show any effect in heterozygous females. Disruptions in the activity of the beta 3-adrenergic receptor in the homozygous male and the heterozygous or homozygous female appear to have a profound effect in animal models, but a limited consequence in human physiology. Association with obesity or diabetes in humans is still controversial. This difference between animal and human models may be explained by the different quantity and distribution of metabolically active brown adipose tissue in the two.
Topics: Animals; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-3
PubMed: 10714358
DOI: 10.1016/s0188-4409(99)00077-6 -
Proceedings of the National Academy of... Dec 2020The β adrenergic receptor (βAR) is an archetypal G protein coupled receptor (GPCR). One structural signature of GPCR activation is a large-scale movement (ca. 6 to 14...
The β adrenergic receptor (βAR) is an archetypal G protein coupled receptor (GPCR). One structural signature of GPCR activation is a large-scale movement (ca. 6 to 14 Å) of transmembrane helix 6 (TM6) to a conformation which binds and activates a cognate G protein. The βAR exhibits a low level of agonist-independent G protein activation. The structural origin of this basal activity and its suppression by inverse agonists is unknown but could involve a unique receptor conformation that promotes G protein activation. Alternatively, a conformational selection model proposes that a minor population of the canonical active receptor conformation exists in equilibrium with inactive forms, thus giving rise to basal activity of the ligand-free receptor. Previous spin-labeling and fluorescence resonance energy transfer experiments designed to monitor the positional distribution of TM6 did not detect the presence of the active conformation of ligand-free βAR. Here we employ spin-labeling and pressure-resolved double electron-electron resonance spectroscopy to reveal the presence of a minor population of unliganded receptor, with the signature outward TM6 displacement, in equilibrium with inactive conformations. Binding of inverse agonists suppresses this population. These results provide direct structural evidence in favor of a conformational selection model for basal activity in βAR and provide a mechanism for inverse agonism. In addition, they emphasize 1) the importance of minor populations in GPCR catalytic function; 2) the use of spin-labeling and variable-pressure electron paramagnetic resonance to reveal them in a membrane protein; and 3) the quantitative evaluation of their thermodynamic properties relative to the inactive forms, including free energy, partial molar volume, and compressibility.
Topics: Magnetic Resonance Spectroscopy; Models, Molecular; Pressure; Protein Conformation, alpha-Helical; Receptors, Adrenergic, beta-2; Thermodynamics
PubMed: 33257561
DOI: 10.1073/pnas.2013904117 -
Methods in Molecular Biology (Clifton,... 2000
Review
Topics: Animals; Blotting, Northern; Humans; RNA, Messenger; Receptors, Adrenergic
PubMed: 10685406
DOI: 10.1385/1-59259-684-3:129 -
The Journal of Pharmacology and... Aug 2001The adrenergic receptors play a key role in the modulation of sympathetic nervous system activity as well as a site of action for many therapeutic agents. The... (Review)
Review
The adrenergic receptors play a key role in the modulation of sympathetic nervous system activity as well as a site of action for many therapeutic agents. The alpha1-adrenergic receptor subtypes (alpha1A-, alpha1B-, alpha1D) are the prime mediators of smooth muscle contraction and hypertrophic growth, but their characterization in both binding and function have lagged the other adrenergic family members. Although they are derived from a related ancestral gene and all nine adrenergic receptor family members bind the endogenous ligands, epinephrine and norepinephrine, with roughly similar affinities, there are major differences in the mode of binding, second messenger utilization, and physiological effects of the alpha1-subtypes compared with beta- or alpha2-subtypes. Here, we review the recent literature on aspects of its binding pocket and how it differs from the beta-adrenergic receptor paradigms. We also review the signaling components and aspects of its function and provide new insights into its roles in smooth muscle, growth, neurological, and cardiovascular function.
Topics: Adrenergic alpha-Antagonists; Animals; Humans; Receptors, Adrenergic, alpha-1; Signal Transduction
PubMed: 11454900
DOI: No ID Found -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Jun 2007The prevalent rates of overweight and obesity are steadily increasing all over the world. Previous studies of some candidate genes have indicated that most of the genes... (Review)
Review
The prevalent rates of overweight and obesity are steadily increasing all over the world. Previous studies of some candidate genes have indicated that most of the genes are associated with obesity in human adipose tissue. As much as 40% of the variations in body mass could be attributed to genetic difference. The beta-adrenergic receptor (beta-AR) plays a major role in the regulation of energy balance in humans. A high sympathetic nervous system activity has been shown to be associated with obesity and is believed to have pathogenetic relevance. Several common single nucleotide polymorphisms (SNPs) including Gly389Arg in beta(1)-AR, Gln27Glu in beta(2)-AR, and Trp64Arg in beta(3)-AR in humans could alter receptor function and these variations of beta-ARs were shown to have certain association with obesity. Here we summarize the genetic polymorphisms of human beta-ARs and their potential impacts to obesity.
Topics: Humans; Mutation, Missense; Obesity; Polymorphism, Single Nucleotide; Receptors, Adrenergic; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Receptors, Adrenergic, beta-3
PubMed: 17611309
DOI: No ID Found -
Masui. the Japanese Journal of... Jan 2008Adrenergic receptor is one of the superfamilies of G-protein-coupled receptor. Its members are homologous in structure and diverse in function and are among the most... (Review)
Review
Adrenergic receptor is one of the superfamilies of G-protein-coupled receptor. Its members are homologous in structure and diverse in function and are among the most pursued targets for drug development. Molecular pharmacological studies have established classification, structure, and function of adrenergic receptors approximately 100 years after Dr Langley had first referred to the philosophical concept of receptive substance. Molecular technology can identify mediating receptor subtype for each function. In this review, I focus on the current and evolving understanding of adrenergic receptor, especially relevant to the clinical settings such as heart failure and inverse agonism, and research topics such as desensitization and polymorphism, for all anesthesiologists.
Topics: Animals; G-Protein-Coupled Receptor Kinase 2; Heart Failure; Mice; Polymorphism, Genetic; Receptors, Adrenergic
PubMed: 18214003
DOI: No ID Found -
Physiological Reviews Apr 1992
Review
Topics: Animals; Humans; Lung; Receptors, Adrenergic, beta
PubMed: 1313586
DOI: 10.1152/physrev.1992.72.2.323