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1.
SNAREs and SNARE regulators in membrane fusion and exocytosis 总被引:21,自引:0,他引:21
J. E. Gerst 《Cellular and molecular life sciences : CMLS》1999,55(5):707-734
Eukaryotes have a remarkably well-conserved apparatus for the trafficking of proteins between intracellular compartments
and delivery to their target organelles. This apparatus comprises the secretory (or ‘protein export’) pathway, which is responsible
for the proper processing and delivery of proteins and lipids, and is essential for the derivation and maintenance of those
organelles. Protein transport between intracellular compartments is mediated by carrier vesicles that bud from one organelle
and fuse selectively with another. Therefore, organelle-specific trafficking of vesicles requires specialized proteins that
regulate vesicle transport, docking and fusion. These proteins are generically termed SNAREs and comprise evolutionarily conserved
families of membrane-associated proteins (i.e. the synaptobrevin/VAMP, syntaxin and SNAP-25 families) which mediate membrane
fusion. SNAREs act at all levels of the secretory pathway, but individual family members tend to be compartment-specific and,
thus, are thought to contribute to the specificity of docking and fusion events. In this review, we describe the different
SNARE families which function in exocytosis, as well as discuss the role of possible negative regulators (e.g. ‘SNARE-masters’)
in mediating events leading to membrane fusion. A model to illustrate the dynamic cycling of SNAREs between fusion-incompetent
and fusion-competent states, called the SNARE cycle, is presented.
Received 8 October 1998; received after revision 26 November 1998; accepted 26 November 1998 相似文献
2.
J. -L. Carpentier P. Gorden A. Robert L. Orci 《Cellular and molecular life sciences : CMLS》1986,42(7):734-744
Conclusion The insulin receptor is an integral protein of the plasma membrane of the cell. It is composed of two subunits: an subunit, which binds the hormone, and a subunit which is a tyrosine specific protein kinase capable of undergoing autophosphorylation. These independent subunits are synthesized by way of a higher molecular weight single chain precursor and thus are the product of a single gene29, 49, 85 localized to chromosome 1929, 91. Assuming that the insulin receptor is synthesized in the same fashion as other integral membrane glycoproteins, then the nucleus, the rough endoplasmic reticulum, and the Golgi apparatus are involved in its biosynthesis. Further, there must be some form of transport of the mature receptor subunits to the plasma membrane where they are inserted.By contrast, the endocytotic route involves coated pits, coated vesicles, large clear vesicles or endosomes, multivesicular bodies and other lysosomal forms. In addition, it is possible that some other as yet unidentified organelle is involved in recycling (fig. 8). At the present time, with respect to the insulin receptor, the biosynthetic pathway and the endocytotic pathway appear to be separate. Further, it does not appear that either pathway, i. e. synthesis or endocytosis, exerts a regulatory function over the other. 相似文献
3.
Spampinato S Di Toro R Alessandri M Murari G 《Cellular and molecular life sciences : CMLS》2002,59(12):2172-2183
In this study, we examined agonist-induced internalization, recycling and signalling (measure of cAMP levels) of the cloned human nociceptin receptor (hNOP) expressed in CHO-K1 cells. Internalization was proven by a receptor-binding assay on viable cells. The agonist nociceptin/orphanin FQ (NC) promoted rapid internalization of the hNOP receptor (approximately 78% of cell surface receptors were lost after 2 min exposure to 1 microM NC) in a clathrin- and ATP-dependent manner. Internalization was more rapid and marked in CHO-K1 cells than, as we previously reported, in SK-N-BE cells. This difference may be related to higher levels of beta-arrestin isoforms detected in CHO-K1 than in SK-N-BE cells. hNOP receptor internalization was partially reversible and recycling occurred in the presence of the agonist; receptor recycling was dependent on okadaic acid-sensitive phosphatases and was blocked by monensin. Confocal microscopy analysis confirmed the internalization and the recycling back to the plasma membrane of an epitope-tagged hNOP receptor expressed in CHO-K1 cells. These receptors underwent rapid desensitization upon agonist challenge: NC efficacy in inhibiting forskolin-stimulated cAMP production was significantly reduced 10 min after exposure and correlated with the rate of receptor internalization. Moreover, we observed that blockade of hNOP receptor recycling by monensin would cause a more prolonged and relevant desensitization of this receptor. Thus, the dynamic cycle between hNOP receptor activation, internalization and recycling determines the activity of this receptor on the cell surface. 相似文献
4.
H. Van Dael 《Cellular and molecular life sciences : CMLS》1998,54(11):1217-1230
Protein folding is an extremely active field of research where biology, chemistry, computer science and physics meet. Although
the study of protein-folding intermediates in general and equilibrium intermediates in particular has grown considerably in
recent years, many questions regarding the conformational state and the structural features of the various partially folded
intermediate states remain unanswered. Performing kinetic measurements on proteins that have had their structures modified
by site-directed mutagenesis, the so-called protein-engineering method, is an obvious way to gain fine structural information.
In the present review, this method has been applied to a variety of proteins belonging to the lysozyme/α-lactalbumin family. Besides recombinants obtained by point mutations of individual critical residues, chimeric proteins in
which whole structural elements (10 – 25 residues) from α-lactalbumin were inserted into a human lysozyme matrix are examined. The conformational properties of the equilibrium intermediate
states are discussed together with the structural characterization of the partially unfolded states encountered in the kinetic
folding pathway.
Received 28 May 1998; received after revision 6 July 1998; accepted 6 July 1998 相似文献
5.
Wnt-frizzled signaling to G-protein-coupled effectors 总被引:2,自引:0,他引:2
6.
Evert Karlsson 《Cellular and molecular life sciences : CMLS》1973,29(11):1319-1327
Conclusion I have discussed in this article only the most active toxins, with the result that many interesting substances have been omitted, e.g. the toxins from bee and wasp venoms (apamin, melittin, etc.), of many amphibians (bufotoxins, etc.), ciguatoxins, and many more. Poisons are found in every phylum except birds. Shrews exemplify venomous mammals. One gets a good illustration of the number of poisonous animals by studying the monumental and impressive work byHalstead
106 which consequently excludes terrestrial animals. An interesting fact in this connection is that there are about 20,000 species of spiders, most of which are poisonous.A toxin ranking list has to be included in an article of this kind. The list is, of course, far from complete. Data on molecular weights, mouse lethal doses, etc. are lacking for many potent toxins, such as the dysentery toxin, a neurotoxin with a toxicity comparable to that of the botulinus toxins107, the toxins from the jelly fishChironex fleckeri
106.A comparison on molar basis gives a better notion of the toxicities. Curare has about 1/30 of the toxicity of the curarimimetic snake venom neurotoxins, clearly indicating that curare has a much lower affinity for the acetylcholine receptor.Toxic organisms have developed during millions of years more and more refined toxins, and this evolution has probably brought into existence toxins against every physiological function. Neurochemistry is to a great extent unexplored. Progress in this field will in the nearest future depend on specific toxins from various natural sources. Toxins from spiders, scorpions, snakes, frogs, and fishes are therefore not mere curiosities but valuable tools for research on the molecular mechanisms of neural function and synaptic transmission. 相似文献
7.
Sánchez-Margalet V González-Yanes C Santos-Alvarez J Najib S 《Cellular and molecular life sciences : CMLS》1999,55(1):142-147
Insulin action is initiated by binding to its cognate receptor, which then triggers multiple cellular responses by activating
different signaling pathways. There is evidence that insulin receptor signaling may involve G protein activation in different
target cells. We have studied the activation of G proteins in rat hepatoma (HTC) cells. We found that insulin stimulated binding
of guanosine 5′-O-(3-thiotriphosphate) (GTP-γ-35S) to plasma membrane proteins of HTC cells, in a dose-dependent manner. This effect was completely blocked by pertussis toxin
treatment of the membranes, suggesting the involvement of G proteins of the Gα
i/Gα
o family. The expression of these Gα proteins was checked by Western blotting. Next, we used blocking antibodies to sort out the specific Gα protein activated by insulin stimulation. Anti-Gα
il,2 antibodies completely prevented insulin-stimulated GTP binding, whereas anti-Gα
o,i3 did not modify this effect of insulin on GTP binding. Moreover, we found physical association of the insulin receptor with
Gα
i1,2 by copurification studies. These results further support the involvement of a pertussis toxin-sensitive G protein in insulin
receptor signaling and provides some evidence of specific association and activation of Gα
i1,2 protein by insulin. These findings suggest that Gα
i1,2 proteins might be involved in insulin action.
Received 23 September 1998; received after revision 23 November 1998; accepted 25 November 1998 相似文献
8.
Phylogeny and rapid Northern and Southern Hemisphere speciation of goldfinches during the Miocene and Pliocene Epochs 总被引:5,自引:0,他引:5
A. Arnaiz-Villena M. Álvarez-Tejado V. Ruíz-del-Valle C. García-de-la-Torre P. Varela M. J. Recio S. Ferre J. Martínez-Laso 《Cellular and molecular life sciences : CMLS》1998,54(9):1031-1041
Mitochondrial cytochrome b (cyt b) from 25 out of 31 extant goldfinches, siskins, greenfinches and redpolls (genus Carduelis) has been sequenced from living samples taken around the world, specimens have also been photographed. Phylogenetic analysis
consistently gave the same groups of birds, and this grouping was generally related to geographical proximity. It has been
supposed that Pleistocene glaciations played a crucial role in the origin of extant diversity and distribution of Northern
Hemisphere vertebrates. Molecular comparison of most extant songbird species belonging to the genus Carduelis does not support this assertion. The fossil record of chicken and pheasant divergence time has been used to calibrate the
molecular clock; cyt b DNA dendrograms suggest that speciation in Carduelinae birds occurred during the Miocene and Pliocene
Epochs (9 – 2 million years ago) in both the Northern and Southern Hemispheres. Only about 4% average amount of nucleotide
substitution per lineage is found between the most distant Carduelis species; this suggests a remarkably rapid radiation when compared with the radiation of other passerine songbird genera.
In addition, a continuum of small songbird speciation may be found during the Miocene Epoch in parallel with speciation of
other orders (i.e. Galliformes, chicken/pheasant). Pleistocene glaciations may have been important in subspeciation (i.e.
Eastern European grey-headed goldfinches/Western European black-headed goldfinches) and also in ice-induced vicariance (isolation)
(i.e. siskin in Western Europe vs. siskin in Far East Asia) around the world. European isolated Serinus citrinella (citril finch) is not a canary, but a true goldfinch. South American siskins have quickly radiated in the last 4 million
years coinciding with the emergence of the Isthmus of Panama; probably, a North American siskin related to C. notata invaded a suitable and varied biotope (the South American island) for Carduelis birds. North American goldfinches may be renamed as siskins, because they have a distant genetic relationship with European
goldfinches. Genus Acanthis could be dropped, and thus redpolls should be separated from twite and linnet, the latter (Europeans) probably being related
to American goldfinches. Also, reproductive barriers are observed between closely related species and not between other more
distant ones. Finally, a tentative classification for genus Carduelis species is suggested.
Received 6 March 1998; received after revision 3 July 1998; accepted 7 July 1998 相似文献
9.
The intracellular signaling pathways mediating the nuclear exclusion of the androgen receptor (AR) by melatonin were evaluated
in PC3 cells stably transfected with the AR. The melatonin-induced nuclear exclusion of the AR by melatonin (100 nM, 3 h)
was blocked by LY 83583 (an inhibitor of guanylyl cyclases). 8-Bromo-cGMP (a cell-permeable cGMP analog), mimicked the effect
of melatonin, as did ionomycin (a calcium ionophore) and PMA [an activator of protein kinase C (PKC)], and their effects were
blocked by GF-109203X (a selective PKC inhibitor). BAPTA (an intracellular calcium chelator) blocked the effects of melatonin
and 8-bromo-cGMP but not of PMA. Inhibition or activation of the protein kinase A pathway did not affect basal or melatonin-mediated
AR localization. We conclude that the melatonin-mediated rise in cGMP elicits AR nuclear exclusion via a pathway involving
increased intracellular calcium and PKC activation. These results define a novel signaling pathway that regulates AR localization
and androgen responses in target cells.
Received 31 July 2001; received after revision 18 September 2001; accepted 30 October 2001 相似文献
10.
Uteroglobin: a novel cytokine? 总被引:18,自引:0,他引:18
A. B. Mukherjee G. C. Kundu G. Mantile-Selvaggi C.-J. Yuan A. K. Mandal S. Chattopadhyay F. Zheng N. Pattabiraman Z. Zhang 《Cellular and molecular life sciences : CMLS》1999,55(5):771-787
Blastokinin or uteroglobin (UG) is a steroid-inducible, evolutionarily conserved, multifunctional protein secreted by the mucosal epithelial of virtually all mammals. It is present in the blood and in other body fluids including urine. An antigen immunoreactive to UG antibody is also detectable in the mucosal epithelia of all vertebrates. UG-binding proteins (putative receptor), expressed on several normal and cancer cell types, have been characterized. The human UG gene is mapped to chromosome 11q12.2 13.1, a region that is frequently rearranged or deleted in many cancers. The generation of UG knockout mice revealed that disruption of this gene causes: (i) severe renal disease due to an abnormal deposition of fibronectin and collagen in the glomeruli; (ii) predisposition to a high incidence of malignancies; and (iii) a lack of polychlorinated biphenyl binding and increased oxygen toxicity in the lungs. The mechanism(s) of UG action is likely to be even more complex as it also functions via a putative receptor-mediated pathway that has not yet been clearly defined. Molecular characterization of the UG receptor and signal transduction via this receptor pathway may show that this protein belongs to a novel cytokine/chemokine family. 相似文献
11.
Effects of pCai and pHi on cell-to-cell coupling 总被引:1,自引:0,他引:1
M L Pressler 《Experientia》1987,43(10):1084-1091
Internal longitudinal resistance (ri), a determinant of cardiac conduction, is affected by changes in intracellular calcium and protons. However, the role and mechanism by which H+ and Ca2+ may modulate ri is uncertain. Cable analysis was performed in cardiac Purkinje fibers to measure ri during various interventions. In some experiments, intracellular pH (pHi) was recorded simultaneously to study the pHi-ri relation. Both intracellular Ca2+ and H+ independently modified ri. However, internal resistance of cardiac fibers was insensitive to pHi changes compared to other tissues. A latent period preceded the pHi-related changes in ri and the amount of change depended upon methodology. The results suggest that direct action of protons or ri may be subordinate to other regulatory processes. Ionic regulation of internal longitudinal resistance may occur by more than one mechanism: i) direct cationic binding to sites on junctional membrane proteins; and ii) H+- or Ca2+-dependent phosphorylation of junctional proteins. 相似文献
12.
Melvin Cohn 《Cellular and molecular life sciences : CMLS》2014,71(11):2033-2045
The existence of antigen-receptors, BCR, and T cell antigen-receptors, that are “polyreactive”, necessitates a rethinking of its effect on two problems faced by the “adaptive” immune system: the self (S)–nonself (NS) discrimination and the determination of effector class. Here, we will concentrate on the impact of polyreactivity on the S–NS discrimination. The anti-S cells interacting with S (i.e., responding to Signal 1) are on the pathway to inactivation. Before irreversibility sets in, these cells can be activated by a second signal (Signal 2) from an effector T-helper (eTh). As these polyreactive anti-S cells express anti-NS specificities, they can be activated by recognition of NS-epitopes in the host’s normal immunogenic load with the potential to result in autoimmunity. This problem is delineated using a discrete structural model, the corollaries of which are: (1) a two-step pathway for the purging of anti-S cells (i.e., the S–NS discrimination), and (2) defensible contexts within which to view the phenomena of receptor editing, anergy, and dual receptor cells. 相似文献
13.
The effects of environmental hormones on reproduction 总被引:9,自引:0,他引:9
B. J. Danzo 《Cellular and molecular life sciences : CMLS》1998,54(11):1249-1264
Considerable attention has been given in the past few years to the possibility that man-made chemicals (xenobiotics) in the
environment may pose a hazard to human reproductive health. The endocrine-disrupting effects of many xenobiotics can be interpreted
as interference with the normal regulation of reproductive processes by steroid hormones. Evidence reviewed here indicates
that xenobiotics bind to androgen and oestrogen receptors in target tissues, and to androgen-binding protein and to sex hormone-binding
globulin. Although environmental chemicals have weak hormonal activity, their ability to interact with more than one steroid-sensitive
pathway provides a mechanism by which their hazardous nature can be augmented. A given toxicant may be present in low concentration
in the environment and, therefore, harmless. However, we are not exposed to one toxicant at a time, but, rather, to all of
the xenobiotics present in the environment. Therefore, numerous potential agonists/antagonists working together through several
steroid-dependent signalling pathways could prove to be hazardous to human reproductive health.
Received 25 March 1998; received after revision 15 June 1998; accepted 15 June 1998 相似文献
14.
Ernst S Zobiack N Boecker K Gerke V Rescher U 《Cellular and molecular life sciences : CMLS》2004,61(13):1684-1692
The formyl peptide-like receptor FPRL1 is a member of the chemoattractant subfamily of G protein- coupled receptors involved in regulating leukocyte migration in inflammation. To elucidate mechanisms underlying the internalization of ligand-bound FPRL1 and possible receptor recycling, we characterized the endocytic itinerary of FPRL1. We show that agonist-triggered internalization from the plasma membrane into intracellular compartments is prevented by perturbation of clathrin-mediated endocytosis, such as expression of the dominant-negative clathrin Hub mutant, siRNA-mediated depletion of cellular clathrin and expression of a dominant-negative mutant of the large GTPase dynamin. Internalized FPRL1 co-localized with endocytosed transferrin and the small GTPases Rab4 and Rab11 in vesicular structures most resembling recycling endosomes. Recycling of FPRL1 was significantly reduced by pretreatment with PI3-kinase inhibitors. Thus, ligand-bound FPRL1 undergoes primarily clathrin-mediated and dynamin-dependent endocytosis and the receptor recycles via a rapid PI3-kinase-sensitive route as well as pathways involving perinuclear recycling endosomes.Received 19 March 2004; received after revision 26 April 2004; accepted 12 May 2004 相似文献
15.
Scavenger receptor family proteins: roles for atherosclerosis, host defence and disorders of the central nervous system 总被引:11,自引:1,他引:10
Y. Yamada T. Doi T. Hamakubo T. Kodama 《Cellular and molecular life sciences : CMLS》1998,54(7):628-640
In this review, we summarize the structure and function of the scavenger receptor family of proteins including class A (type
I and II macrophage scavenger receptors, MARCO), class B (CD36, scavenger receptor class BI), mucinlike (CD68/macrosialin,
dSR-CI) and endothelial (LOX-1) receptors. Two motifs have been identified as ligand-binding domains a charged collagen structure
of type I and II receptors, and an immunodominant domain of CD36. These structures can recognize a wide range of negatively
charged macromolecules, including oxidized low-density lipoproteins, damaged or apoptotic cells, and pathogenic microorganisms.
After binding, these ligands can be either internalized by endocytosis or phagocytosis, or remain at the cell surface and
mediate adhesion or lipid transfer through caveolae. Under physiological conditions, scavenger receptors serve to scavenge
or clean up cellular debris and other related materials, and they play a role in host defence. In pathological states, they
mediate the recruitment, activation and transformation of macrophages and other cells which may be related to the development
of atherosclerosis and to disorders caused by the accumulation of denatured materials, such as Alzheimer's disease.
Received 17 September 1997; received after revision 16 March 1998; accepted 17 March 1998 相似文献
16.
Anthrax toxins 总被引:3,自引:0,他引:3
Though its lethal effects were ascribed to an exotoxin almost half a century ago, the pathogenesis of anthrax has yet to
be satisfactorily explained. Subsequent work has led to the molecular identification and enzymatic characterization of three
proteins that constitute two anthrax toxins. Protective antigen binds an as yet unknown cell receptor and mediates the entry
of the other two components to the cytoplasm via the endosomal pathway. Edema factor, so named for its ability to induce edema,
is a Ca2+/calmodulin-dependent adenylate cyclase. Lethal factor, the dominant virulence factor associated with the toxin, proteolytically
inactivates mitogen-activated protein kinase kinases, key players in signal transduction. We describe the fascinating work
that has led to these discoveries and discuss their relevance to our understanding of the pathogenesis of anthrax.
Received 6 January 1999; received after revision 8 March 1999; accepted 9 March 1999 相似文献
17.
The structure and function of heterotrimeric G protein subunits is known in considerable detail. Upon stimulation of a heptahelical
receptor by the appropriate agonists, the cognate G proteins undergo a cycle of activation and deactivation; the α-subunits and the βγ-dimers interact sequentially with several reaction partners (receptor, guanine nucleotides and effectors as well as regulatory
proteins) by exposing appropriate binding sites. For most of these domains, low molecular weight ligands have been identified
that either activate or inhibit signal transduction. These ligands include short peptides derived from receptors, G protein
subunits and effectors, mastoparan and related insect venoms, modified guanine nucleotides, suramin analogues and amphiphilic
cations. Because compounds that act on G proteins may be endowed with new forms of selectivity, we propose that G protein
subunits may therefore be considered as potential drug targets.
Received 18 September 1998; received after revision 6 November 1998; accepted 11 November 1998 相似文献
18.
Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts 总被引:21,自引:0,他引:21
Cyclosporine A therapy for prophylaxis against graft rejection revolutionized human organ transplantation. The immunosuppressant
drugs cyclosporin A (CsA), FK506 and rapamycin block T-cell activation by interfering with the signal transduction pathway.
The target proteins for CsA and FK506 were found to be cyclophilins and FK506-binding proteins, (FKBPs), respectively. They
are unrelated in primary sequence, although both are peptidyl-prolyl cis-trans isomerases catalyzing the interconversion of
peptidyl-prolyl imide bonds in peptide and protein substrates. However, the prolyl isomerase activity of these proteins is
not essential for their immunosuppressive effects. Instead, the specific surfaces of the cyclophilin-CsA and FKBP-FK506 complexes
mediate the immunosuppressive action. Moreover, the natural cellular functions of all but a few remain elusive. In some cases
it could be demonstrated that prolyl isomerization is the rate-limiting step in protein folding in vitro, but many knockout
mutants of single and multiple prolyl isomerases were viable with no detectable phenotype. Even though a direct requirement
for in vivo protein folding could not be demonstrated, some important natural substrates of the prolyl isomerases are now
known, and they demonstrate the great variety of prolyl isomerization functions in the living cell: (i) A human cyclophilin
binds to the Gag polyprotein of the human immunodeficiency virus-1 (HIV-1) virion and was found to be essential for infection
with HIV to occur, probably by removal of the virion coat. (ii) Together with heat shock protein (HSP) 90, a member of the
chaperone family, high molecular weight cyclophilins and FKBPs bind and activate steroid receptors. This example also demonstrates
that prolyl isomerases act together with other folding enzymes, for example the chaperones, and protein disulfide isomerases.
(iii) An FKBP was found to act as a modulator of an intracellular calcium release channel. (iv) Along with the cyclophilins
and FKBPs, a third class of prolyl isomerases exist, the parvulins. The human parvulin homologue Pin1 is a mitotic regulator
essential for the G2/M transition of the eukaryotic cell cycle. These findings place proline isomerases at the intersection
of protein folding, signal transduction, trafficking, assembly and cell cycle regulation.
Received 18 September 1998; received after revision 4 November 1998; accepted 23 November 1998 相似文献
19.
Ribosome-inactivating proteins: progress and problems 总被引:11,自引:0,他引:11
Ribosome-inactivating proteins (RIPs), mostly from plants, are enzymes which depurinate rRNA, thus inhibiting protein synthesis.
They also depurinate other polynucleotide substrates. The biological activity of RIPs is not completely clarified, and sometimes
independent of the inhibition of protein synthesis. There are differences in the cytotoxicity of RIPs and, consequently, in
their toxicity to animals. Some RIPs are potent toxins, the best known being ricin, a potential biological weapon. New toxins
have recently been identified. RIPs cause apoptotic and necrotic lesions, and induce production of cytokines causing inflammation.
RIPs are potentially useful in agriculture and medicine because (i) they have antiviral activity and (ii) they are used for
the preparation of conjugates with antibodies (‘immunotoxins’) or other carriers, rendering them specifically toxic to the
cell target of the carrier, which may be helpful in therapy. The distribution, mechanism of action and role in nature of RIPs
are not completely understood, and we can expect several future developments in their practical application.
Received 17 February 2006; received after revision 23 March 2006; accepted 2 May 2006 相似文献
20.
Towards an understanding of the role of glutamate in neurodegenerative disorders: energy metabolism and neuropathology 总被引:3,自引:0,他引:3
It is thought that impairment, of energy metabolism that results in deterioration of membrane function, leading to loss of the Mg2+ block on NMDA receptors, and allowing persistent activation of these receptors by glutamate, might be a cause of neuronal death in neurodegenerative disorders. Studies in rodents using mitochondrial respiratory chain toxins, such as aminooxyacetic acid, 1-methyl-4-phenylpyridinium, malonic acid and 3-nitropropionic acid, suggest that such processes may indeed be involved in neurotoxicity. Striatal and nigral degeneration induced by mitochondrial toxins in rodents resembles the neuropathology seen in humans suffering from Huntington's or Parkinson's disease, and can be prevented either by decortication or by NMDA receptor antagonists. Such experimental observations suggest that glutamate may be involved in neuronal death leading to neurodegenerative disorders in humans. If so, glutamate antagonists may offer a therapeutic approach for retarding the progression of these disabling disorders. 相似文献