ISSN:0892-6638    

DOI:10.1096/fasebj.6.6.1312044

出版商:Wiley    

年代:1992

数据来源: WILEY

ISSN:0892-6638    

DOI:10.1096/fasebj.6.6.1544538

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Structural studies of muscle glycogen phosphorylase during the last two decades have provided a detailed mechanism for the molecular basis of the control by phosphorylation and by allosteric effectors and the catalytic mechanism. Control by phosphorylation is effected by a disorder to order transition of the NH2‐terminal residues that promotes localized changes in the structure of the protein at the region of subunit‐subunit contacts and larger changes in the quaternary structure. The covalently attached phosphate group acts like an allosteric effector but the full manifestation of the response is also dependent on the NH2‐terminal tail residues. The noncovalently bound allosteric effectors produce similar shifts in the structural states although these are bound at sites that are remote from the serine‐phosphate site. The communication from these sites to the catalytic site is through long‐range interactions that result in activation of the enzyme through opening access to the buried catalytic site and through creation of the substrate phosphate recognition site by an interchange of an acidic group with a basic group. Recent advances in expression systems have opened the way to a study of properties both for the muscle and other isozymes and other species that should illuminate the different regulatory roles of the enzyme in different tissues and organisms. The allosteric mechanism of activation of phosphorylase by phosphorylation may be relevant to other enzymes although it is now known that other mechanisms such as electrostatic steric blocking mechanisms also exist.—Johnson, L. N. Glycogen phosphorylase: control by phosphorylation and allosteric effectors.FASEB J.6: 2274‐2282; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.6.1544539

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

In recent years, there has been a great deal of publicity concerning the possible health effects of electric and/or magnetic field exposure. One of the most frequently reported observations after the exposure of animals to either electric or magnetic fields relates to alterations in the metabolism of serotonin (5HT) to melatonin within the pineal gland. This review summarizes these results particularly in animals exposed to intermittently inverted, non‐time varying magnetic fields, i.e., pulsed static magnetic fields. When exposure occurs at night, the convention of 5HT to melatonin is typically depressed, not unlike that after light exposure at night. The mechanisms by which pulsed magnetic fields alter the ability of the pineal to convert 5HT to the chief pineal hormone melatonin remains unknown but may involve effects on any or all of the following: the retinas, the suprachiasmatic nuclei, the peripheral sympathetic nervous system, and the pinealocytes. Results to date suggest that induced electrical currents (eddy currents) produced by the pulsed magnetic fields are particularly detrimental to pineal indoleamine metabolism and may be an important causative factor in the metabolic changes measured. The physiological consequences of perturbations in the melatonin rhythm induced by magnetic field exposure remain unknown.—Reiter, R. J.; Richardson, B. A. Magnetic field effects on pineal indoleamine metabolism and possible biological consequences.FASEB J.6: 2283‐2287; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.6.1544540

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

The nuclear pore complex is at the crossroads of macromolecular traffic across the nuclear envelope. Our knowledge of the mechanism whereby nuclear transport is mediated by the nuclear pore complex is also at a crossroads; a molecular understanding of this process has major implications for applied medical sciences. This becomes obvious with the realization that nuclear proteins are synthesized in the cytoplasm and yet function in the nucleus, and that RNA is transcribed in the nucleus but translated in the cytoplasm. Thus, control of macromolecular traffic across the nuclear membrane is an important means for altering the levels and activities of such molecules as steroid hormone receptors, transcription factors, and enzymes involved in DNA replication. Nuclear proteins have been found to contain nuclear localization sequences (NLS) rich in basic amino acids, which target them for transport through the nuclear pore to the nucleus. It is also clear that a group of novel glycoproteins having a unique carbohydrate modification are required for transport across the nuclear pore complex. However, the mechanism by which the NLS is recognized to mediate transport across the nuclear envelope is poorly understood. It is the aim of this brief review to attempt a synthesis of what is known of this mechanism and what may be newly inferred on the basis of current experimental data.—Hanover, J. A. The nuclear pore: at the crossroads.FASEB J.6: 2288‐2295; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.6.1312045

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Platelet‐activating factor (PAF) is the most potent phospholipid agonist known to date. Radioligand binding studies using [3H]PAF and structurally different PAF antagonists have provided the characteristics of PAF receptor(s) and its heterogeneity. Although efforts have been made to isolate the receptor, it was not until the recent cloning of the PAF receptor that the molecular architecture of the receptor can be visualized. The receptor shows homology to the G protein‐coupled receptors with seven transmembrane spanning segments. Several serine, threonine, and tyrosine residues are present at the cytoplasmic side, which could serve as sites for phosphorylation. PAF activates GTPase, causes phospholipid turnover via phospholipases C, D, and A2pathways and also activates protein kinase C and tyrosine kinase. Further, PAF stimulates Ca2+mobilization some of which may occur via receptor operated channel. Second messengers generated by these multiple signalling pathways play role (or roles) in PAF responses and in the PAF induced expression of primary response genes. These recent developments throw light on the PAF receptor and its signal transduction mechanisms.—Shukla, S. D. Platelet‐activating factor receptor and signal transduction mechanisms.FASEB J.6: 2296‐2301; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.6.1312046

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

O6‐Alkylguanines, important DNA adducts formed by alkylating agents, can lead to mutations and to cell death unless repaired. The major pathway of repair involves the transfer of the alkyl group from the DNA to a cysteine acceptor site in the proteinO6‐alkylguanine‐DNA alkyltransferase. The alkyltransferase brings about this transfer without need for cofactors and the DNA is restored completely by the action of a single protein, but the cysteine acceptor site is not regenerated and the number ofO6‐alkylguanines that can be repaired is equal to the number of active alkyltransferase molecules. The alkylated form of the protein is unstable in mammalian cells and is degraded rapidly. Cloning of the cDNAs for the alkyltransferase proteins from bacteria, yeast, and mammals indicates a significant similarity, particularly in the region surrounding the cysteine acceptor site. There is a major difference in the regulation of the alkyltransferase between mammalian cells and certain bacteria, where it is induced as part of the adaptive response to alkylating agents. Regulation of the content of alkyltransferase in mammalian cells differs with species and cell type and, in some cases, the level of the protein is increased by exposure to alkylating agents or X rays. A significant fraction of human tumor cell lines do not express the alkyltransferase gene and, thus, are much more sensitive to mutagenesis and killing by alkylating agents. The frequency of primary tumor cells that lack alkyltransferase protein is not yet clear. However, it is known that the level of alkyltransferase in tumors is a significant factor in resistance to both methylating agents and bifunctional chloroethylating agents. Inactivation of the alkyltransferase, which can be brought about by pretreatment with an alkylating agent or by exposure toO6‐benzylguanine (a powerful nontoxic inhibitor), sensitizes tumor cells to these chemotherapeutic alkylating agents and may prove a useful therapeutic strategy.—Pegg, A. E.; Byers, T. L. Repair of DNA containingO6‐alkylguanine.FASEB J.6: 2302‐2310; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.6.1544541

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Neuroactive steroids are natural or synthetic steroids that rapidly alter the excitability of neurons by binding to membrane‐bound receptors such as those for inhibitory and (or) excitatory neurotransmitters. The best‐studied neuroactive steroids are a series of sedative‐hypnotic 3α‐hydroxy ring A‐reduced pregnane steroids that include the major metabolites of progesterone and deoxycorticosterone, 3α‐hydroxy‐5α‐pregnan‐20‐one (allopregnanolone) and 3α,21‐dihydroxy‐5α‐pregnan‐20‐one (allotetrahydroDOC), respectively. These 3α‐hydroxysteroids do not interact with classical intracellular steroid receptors but bind stereoselectively and with high affinity to receptors for the major inhibitory neurotransmitter in brain, γ‐aminobutyric acid (GABA). Biochemical and electrophysiological studies have shown that these steroids markedly augment GABA‐activated chloride ion currents in a manner similar (but not identical) to that of anesthetic barbiturates. Several steroids have also been observed to have convulsant or proconvulsant properties, including the synthetic amidine 3α‐hydroxy‐16‐imino‐5β‐17‐azaandrostan‐11‐one (RU5135) and the natural sulfate esters of pregnenolone and dehydroepiandrosterone. Several of these have been shown to be bicuculline or picrotoxin‐like GABAAreceptor antagonists. Examples of steroids that alter neuronal excitability rapidly by augmenting or inhibiting excitatory amino acid receptor‐mediated responses have also been reported. Recently, allopregnanolone and allotetrahydroDOC have also been measured in brain and plasma where their levels have been shown to fluctuate in response to stress and during the estrous and menstrual cycles of rats and humans, respectively. Although the major fraction of allopregnanolone in tissue, including brain, is of adrenal and/or ovarian origin, appreciable levels of allopregnanolone can still be measured in the brains of adrenalectomized and/or oophorectomized animals. Receptor‐active neurosteroids may represent an important class of neuromodulators that can rapidly alter central nervous system excitability via novel nongenomic mechanisms.—Paul, S. M.; Purdy, R. H. Neuroactive steroids.FASEB J.6: 2311‐2322; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.6.1347506

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

Rhodopsin is the photoreceptor protein in rod cells of the vertebrate retina and the first member of the class of G protein‐coupled receptors for which the amino acid sequence was determined. Rhodopsin is available in greater quantities than any other receptor of its class and therefore has been studied biochemically and biophysically by methods difficult or impossible to apply to its fellow receptors. Such studies support a model in which rhodopsin consists of seven transmembrane helices that form a binding pocket for its ligand, 11‐cisretinal. Insights into the structure and function of rhodopsin serve as a model for understanding the structure and function of other members of the receptor class. Rhodopsin undergoes a change in conformation upon photoexcitation and activates a G protein, transducin, and is phosphorylated by a receptor‐specific kinase, rhodopsin kinase. The phosphorylated photoactivated rhodopsin is bound by arrestin, thereby terminating activity of the receptor in the signal transduction process. These auxilliary proteins that function with rhodopsin in rod cells serve as models for understanding how other members of the receptor family may function in conjunction with other G proteins, kinases, and arrestin‐like proteins.—Hargrave, P. A.; McDowell, J. H. Rhodopsin and phototransduction: a model system for G protein‐linked receptors.FASEB J.6: 2323‐2331; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.6.1544542

出版商:Wiley    

年代:1992

数据来源: WILEY

摘要:

A major process through which environmental information is transmitted into cells is via activation of protein tyrosine kinases. Receptor tyrosine kinases contain extracellular ligand recognition, single membrane spanning, and cytoplasmic protein tyrosine kinase domains. The cytoplasmic kinase core is flanked by regulatory segments, which in some family members are also inserted into the core kinase domain. Ligand binding initiates receptor signaling from the cell surface. Activated receptors autophosphorylate to remove alternate substrate/inhibitory constraints and to provide loci for assembly of proteins that containSRChomology regions. Information is transmitted and diffused by tyrosine phosphorylation of the assembled proteins and of cellular substrates that include protein kinases with specificity for serine/threonine residues. Signaling, which is strictly ligand‐dependent, is attenuated by down‐regulation of receptors and by feedback inhibitory loops that involve receptor phosphorylation by cellular kinases. The tyrosine kinase receptors are essential for normal growth, development, and reparative processes. Mutations that remove normal regulatory constraints on the ~ 290 amino acid kinase core of these large proteins result in constitutive function and cell transformation.—Cadena, D. L.; Gill, G. N. Receptor tyrosine kinases.FASEB J.6: 2332‐2337; 1992.

ISSN:0892-6638    

DOI:10.1096/fasebj.6.6.1312047

出版商:Wiley    

年代:1992

数据来源: WILEY