共查询到20条相似文献,搜索用时 31 毫秒
1.
A. O. Shpakov 《Journal of Evolutionary Biochemistry and Physiology》2009,45(4):431-446
This review summarizes and analyzes both literature data and results of our own studies on molecular mechanisms of action of natural and artificially created polycationic peptides on functional activity of heterotrimeric G-protein-coupled signal systems. There are considered peptide toxins from insect venom, synthetic peptides that are derivatives of cytoplasmic loops of receptors of the serpentine type as well as artificially created peptides with linear, branched, and dendrimeric structures. Action of most of these peptides on activity of G-proteins is highly selective and these themselves are able to mimic the hormone-activated receptor to be thereby non-hormonal regulators of the signal systems coupled to heterotrimeric G-proteins. 相似文献
2.
Shpakov AO Shpakova EA Tarasenko II Derkach KV Chistiakova OV Vlasov GP 《Rossi?skii fiziologicheski? zhurnal imeni I.M. Sechenova / Rossi?skaia akademiia nauk》2010,96(11):1062-1074
The third intracellular loops of hormonal receptors play the main role in the interaction of majority of the serpentine type receptors with heterotrimeric G-proteins. In recent years, it was shown that synthetic peptides corresponding to membrane-proximal regions of these loops could be selectively influenced with hormonal signal transduction via the receptors homologous to them and trigger signalling cascade in absence of the hormone. For the first time, we succeeded in synthesizing the peptides derived from C-terminal region of the third intracellular loop of the IB-subtype serotonin receptor and studied their influence on serotonin-sensitive adenylyl cyclase system in the rat brain. The peptides 300-316 and 306-316 (the numbers correspond to amino acid positions in the rat IB-subtype serotonin receptor) at micromolar concentrations in absence of hormone-stimulated GTP-binding of Gi,-proteins coupled with the IB-subtype serotonin receptors and inhibited forskolin-stimulated adenylyl cyclase activity. Using selective agonists and antagonists of serotonin receptors it was shown that the peptides 300-316 and 306--316 inhibited serotonin signal transduction via homologous to them receptor and weakly influenced other types of serotonin receptors. The peptide 300-316 is more active compared with its shorter analogue 306-316 in the selectivity and efficiency of action on adenylyl cyclase signalling system regulated via the IB-subtype serotonin receptors. These findings indicate that the regions 300-316 of the IB-subtype serotonin receptor are involved in interaction with Grproteins and consist of the main molecular determinants responsible for serotonin signal transduction to adenylyl cyclase. 相似文献
3.
Shpakov AO 《Rossi?skii fiziologicheski? zhurnal imeni I.M. Sechenova / Rossi?skaia akademiia nauk》2010,96(12):1139-1155
In the review, own results and the data of other authors concerning synthetic peptides corresponding to intracellular and transmembrane regions of receptors of the serpentine type, which are responsible for the interaction with G-proteins and for the formation of ligand-binding site, are analyzed. These peptides affect the basal activity of hormonal signalling systems and the transduction of hormonal signal from the latter with high selectivity and efficiency. Possible molecular mechanisms of the action of peptides, the perspectives of development of a new generation of drugs for the control of endocrine function and physiological processes in the organism on the basis of receptor-based peptides, and their application as functional probes for study of structural-functional organization of hormonal signalling systems are considered. 相似文献
4.
Shpakov AO 《Tsitologiia》2011,53(8):633-644
The peptide strategy, a new direction of molecular endocrinology, includes the synthesis of peptides corresponding to functional regions of signal proteins, the use of the peptides for study of the molecular mechanisms of transduction of hormonal signal into cell ant the development of selective regulators of hormonal signaling systems on the basis of these peptides. The peptide strategy is used for study a wide spectrum of the proteins, components of signal systems, the proteins possessing the catalytic activity in particular, such as tyrosine kinases receptors, the enzymes generating the second messengers, serine/threonine protein kinase, phosphatases. In the first time in the review the data concerning the synthetic peptides, derivatives of the primary structure of proteins with the enzymatic activity, their application for study of the structural-functional organization and the molecular mechanisms of action of signal proteins, and the construction of regulators of fundamental cell processes on the basis of these peptides are analyzed and summarized. 相似文献
5.
A. O. Shpakov M. N. Pertseva 《Journal of Evolutionary Biochemistry and Physiology》2005,41(5):487-505
At present the peptide strategy is used extensively to study molecular mechanisms of interaction between signal proteins, components of hormonal signal systems. The strategy is based on use of synthetic peptides as probes corresponding to functionally important sites of these proteins. This review summarizes and analyzes literature data and results of our own works on use of the peptide strategy for studying functional coupling of receptors of serpentine and tyrosine kinase types with heterotrimeric G-proteins. Alongside with peptides derived from the primary structure of cytoplasmic loops and transmembrane domains as well as from different sites of G-protein α, β, and γ-subunits, natural and synthetic peptides are considered which have no homology with receptors and G-proteins, but are able to affect effectively interaction between them. 相似文献
6.
A. O. Shpakov E. A. Shpakova I. I. Tarasenko K. V. Derkach 《Biochemistry (Moscow) Supplemental Series A: Membrane and Cell Biology》2012,6(1):16-25
Proximal regions of the third intracellular loop (ICL-3) are responsible for the interaction with heterotrimeric G proteins
in most of the serpentine type receptors. The peptides corresponding to these regions are able to activate G proteins in the
absence of hormone and to alter the transduction of hormonal signal via the respective homologous receptor. However, the molecular
mechanisms of action of the peptides, their specificity to receptors and target tissues are currently not well understood.
The goal of this work was to study the receptor and tissue specificity of peptides-derivatives of C-terminal regions of the
ICL-3 of luteinizing hormone receptor (LHR), type 1 relaxin receptor (RXFP1), somatostatin receptors of types 1 and 2 (Som1R and Som2R), and 5-hydroxytryptamine receptors of subtype 1B and type 6 (5-HT1BR and 5-HT6R) on the functional activity of adenylyl cyclase (AC) and GppNHp-binding of G proteins in the brain, myocardium, and testis
of rats. It was shown that the influence of peptides on AC and G proteins is well detected in tissues enriched in homologous
receptors. The effects stimulating AC and GppNHp-binding were most pronounced in the testes for LHR peptide, in the brain
for peptide 5-HT6R, and in all of the tested tissues (but mainly in the myocardium) for the RXFP1 peptide. The AC-inhibiting effects of peptides
Som1R, Som2R and 5-HT1BR, as well as the stimulation of GppNHp binding induced by these peptides, were most pronounced in the brain. In the presence
of the peptides, the AC effects of hormones acting via homologous receptors were significantly attenuated, while the AC effects
of other hormones changed insignificantly. The findings suggest that biological activity of the peptides depends on their
interaction with complementary regions of homologous receptors, which should be taken into account when developing highly
selective regulators of hormonal signaling systems on the basis of these peptides. 相似文献
7.
We and other authors have shown that synthetic peptides corresponding to regions of the third intracellular loop (ICL-3) of receptors of the serpentine type are capable of activating G-protein signaling cascades and trigger them in the absence of hormone. To create on the basis of these peptides the selective regulators of hormonal signaling systems the relationship between their biological activity and secondary structure are studied. It is assumed that most suitable is a helical conformation, which allows the peptide effectively interact with signaling proteins. The aim of this study was to test the biological activity and secondary structure of synthesized by us linear peptides and their dimeric and palmitoylated analogs, corresponding to C-terminal region of the ICL-3 of luteinizing hormone receptor (LHR) and 5-hydroxytryptamine receptor of the type 6 (5-HT6R). It is shown that LHR-peptides at the micromolar concentrations stimulate the basal activity of adenylyl cyclase (AC) and the GTP-binding of G-proteins in the plasma membranes of rat testes, while 5-HT6R-peptides activate AC and G-proteins in the synaptosomal membranes of rat brain. The action of peptides is tissue-specific and observed in the tissues where there are homologous receptors. The most effective were palmitoylated peptides. LHR-peptide reduced the AC stimulatory effect of human chorionic gonadotropin, while 5-HT6R-peptides the effect of 5-HT6R-agonist, EMD-386088, and the action of the peptides was not found in the case of non-homologous receptors. Using circular dichroism spectroscopy it is shown that in neutral (pH 7) and acidic (pH 2) medium all the peptides are exist predominantly in the antiparallel beta-sheet (37-42%) and disordered conformations (33-35%). In alkaline medium (pH 10) in the case palmitoylated peptides the increase of the contribution of the helical conformation to 12-27% was observed. In the presence of trifluoroethanol (10-80%), a helix-forming solvent, the contribution of helical conformation for the majority of peptides was slightly increased (for palmitoylated analogs to 14%), however, in this case the antiparallel beta-sheet and disordered conformation prevailed. The conclusion was made that the lack of clearly expressed ability to form helices in peptides derived the ICLs of receptors did not significantly affect their activity. This is consistent with proposed mechanism of peptides action, whereby peptide interacts with the complementary regions of homologous receptor that does not require the helix formation. 相似文献
8.
E. A. Shpakova E. A. Skvortsova I. I. Tarasenko A. O. Shpakov 《Cell and Tissue Biology》2012,6(3):197-210
We and other authors have shown that synthetic peptides corresponding to regions of the third cytoplasmic loop (CL-3) of receptors of the serpentine type are capable of activating G-protein signaling cascades and triggering them in the absence of a hormone. To create selective regulators of hormonal signaling systems on the basis of these peptides, the relationship between their biological activity and secondary structure is studied. It is suggested that the most suitable is the helical conformation, which allows the peptide to effectively interact with signaling proteins. The goal of this study was to test the biological activity and secondary structure of linear peptides that we synthesized and their dimeric and palmitoylated analogs corresponding to the C-terminal region of CL-3 of luteinizing hormone receptor (LHR) and 5-hydroxytryptamine (serotonin) receptor of type 6 (Ser6R). It is shown that LHR peptides at micromolar concentrations stimulate the basal activity of adenylyl cyclase (AC) and the GTP-binding of G-proteins in plasma membranes of rat testes, while Ser6R peptides activate AC and G-proteins in synaptosomal membranes of rat brain. The action of peptides is tissue-specific and observed in tissues where there are homologous receptors. The most effective were palmitoylated peptides. LHR peptide reduced the AC stimulatory effect of human chorionic gonadotropin, while Ser6R peptides, the effect of Ser6R-agonist, EMD-386088, and the action of the peptides was not found in the case of nonhomologous receptors. Using circular dichroism spectroscopy, it is shown that in the neutral (pH 7) and acidic (pH 2) medium, all the peptides exist predominantly in the antiparallel β-sheet (37–42%) and disordered conformations (33–35%). In the alkaline medium (pH 10) in the case of palmitoylated peptides the increase of the contribution of the helical conformation to 12–27% was observed. In the presence of trifluoroethanol (10–80%), a helix-forming solvent, the contribution of helical conformation for the majority of peptides was slightly increased (for palmitoylated analogs by 14%); however, in this case, the antiparallel β-sheet and disordered conformation prevailed. The conclusion was drawn that the lack of a clearly expressed ability to form helices in peptides derived from CL-3 of receptors did not significantly affect their activity. This is consistent with the proposed mechanism of peptide action, whereby peptide interacts with the complementary regions of homologous receptor that does not require helix formation. 相似文献
9.
A. O. Shpakov E. A. Shpakova 《Biochemistry (Moscow) Supplemental Series B: Biomedical Chemistry》2011,5(3):246-252
In most serpentine type receptors the third intracellular loop (ICL-3) is responsible for the interaction with heterotrimeric
G proteins and for transduction of a hormonal signal to the enzymes, generators of the second messengers. It was found that
the peptides corresponding to ICL-3 influence functional activity of hormonal signaling systems in the absence of the hormone
and, consequently, may be considered as prototypes for the development of selective regulators of these systems. We have originally
synthesized peptides corresponding to the C-terminal regions 255–269 and 240–254 of ICL-3 of type 1 and 2 rat somatostatin
receptors (Som1R and Som2R). Micromolar concentrations of these peptides activated G
i
proteins and inhibited forskolin-stimulated activity of adenylyl cyclase (AC) in rat brain tissues. The peptide 255–269 of
Som1R is a selective antagonist of Som1R, and the peptide 240–254 of Som2R is an agonist of Som1R. The peptide 255–269 of Som1R decreased the regulatory effects of somatostatin and the selective Som1R agonist, CH-275, realized via the homologous receptor, while the peptide 240–254 of Som2R, on the contrary, increased the AC inhibitory effect of CH-275. Both peptides insignificantly influenced regulatory effects
of the Som2R agonist octreotide. Thus, the peptides studied by us are selective regulators of the somatostatin-sensitive AC system. Using
the peptides we have demonstrated that ICL-3 of both Som1R and Som2R includes the main molecular determinants that are responsible for activation of G
i
proteins and regulation of the AC system by somatostatin and its analogues. 相似文献
10.
A. O. Shpakov E. A. Shpakova 《Biochemistry (Moscow) Supplemental Series B: Biomedical Chemistry》2014,8(1):19-26
The regulation of signaling pathways involved in the control of many physiological functions is carried out via the heterotrimeric G protein-coupled receptors (GPCR). The search of effective and selective regulators of GPCR and intracellular signaling cascades coupled with them is one of the important problems of modern fundamental and clinical medicine. Recent data suggest that synthetic peptides and their derivatives, structurally corresponding to the intracellular and transmembrane regions of GPCR, can interact with high efficiency and selectivity with homologous receptors and influence the functional activity of intracellular signaling cascades and fundamental cellular processes controlled by them. GPCR-derived peptides are active in both in vitro and in vivo. They regulate hematopoiesis, angiogenesis and cell proliferation, inhibit tumor growth and metastasis, and prevent the inflammatory diseases and septic shock. These data show great prospects in the development of the new generations of drugs based on GPCR-derived peptides, which can regulate the important functions of the organism. 相似文献
11.
A. O. Shpakov E. A. Shpakova 《Biochemistry (Moscow) Supplemental Series B: Biomedical Chemistry》2009,3(4):351-360
During the last years the low-molecular non-peptidic regulators of the polypeptide hormone receptors containing LGR-repeats
(LGR-receptors) were identified. The review summarizes and systematizes data on structure and molecular mechanisms realizing
the effects of such regulators as agonists and antagonists of the luteinizing, follicle-stimulating and thyroid-stimulating
hormones. The regulators interact with the serpentine domain of LGR-receptors and trigger the receptor-coupled signaling cascades.
Low-molecular agonists and antagonists of the LGR-receptors are considered as a new generation of drugs that can demonstrate
highly sensitive and selective regulation of the functional activity of signaling systems sensitive to pituitary glycoprotein
hormones. These regulators are more available than these hormones and can be used orally. 相似文献
12.
Gilles Dietrich Gérald Gaibelet Régine Capeyrou Jean-Luc Butour Frédéric Pontet Laurent J. Emorine 《Journal of neurochemistry》1998,70(5):2106-2111
Abstract: Recent studies on chimeric μ/δ-, μ/κ- and δ/κ-opioid receptors have suggested that extracellular loops of the receptors were involved in the discriminatory binding of selective ligands by controlling their entry into the transmembrane binding site. Since homochimeric opioid receptors are mostly informative in terms of selectivity, the role of extracellular loops was examined here by studying heterochimeric μ receptors where the totality or parts of extracellular loops were replaced by the corresponding regions of the receptor for angiotensin II. Chimeric μ receptors with extracellular loop EL1 or EL3 originating from the angiotensin receptor had 100-fold decreased affinities for opioids; the length of the first extracellular loop, which is one residue longer in angiotensin than μ receptors, was shown to be responsible for this situation. Substitution of the μ receptor second extracellular loop by that of the angiotensin receptor diminished by ∼10-fold the affinities for opioids. Since all chimeras had altered affinities for selective and nonselective ligands, we propose that extracellular domains of the μ receptor, particularly the first and third loops, constrain the relative positioning of the connected transmembrane domains where selective as well as nonselective contact points form the opioid binding site. 相似文献
13.
The signal systems of the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, coupled to heterotrimeric G-proteins and sensitive to pheromones and alimentary molecules, are prototypes of hormonal signal systems of the higher vertebrate animals and are widely used in studies on molecular mechanisms of their functioning. This review summarizes and analyzes data on structural-functional organization of the first two components of these systems—receptors of the serpentine type and heterotrimeric G-proteins; mechanisms of functional coupling of receptors and G-proteins both between each other and to other signal proteins are discussed. It has been shown that at the early stages of evolution of signaling systems, at the yeast level, various models of transduction of signals into the cell were tested; many of them differ essentially from the classic model of the three-component, G-protein-coupled signal system of the higher vertebrates. 相似文献
14.
Nakanishi S 《IUBMB life》2006,58(5-6):349-357
This paper reviews our studies that have addressed the molecular mechanisms underlying the biosynthesis and reception of extracellular signaling molecules and integrative mechanisms of extracellular-intracellular signaling transmission in biological systems. We introduced recombinant DNA technology into the neuroendocrine system and established the concept that a single peptide precursor encompasses multiple biologically active peptides and brings about coordinate functions in various biological systems. We then developed a novel functional cloning of membrane receptors and ion channels by combining an oocyte expression system with electrophysiology. We molecularly elucidated not only various peptide receptors, including the first demonstration of the molecular entity of a G protein-coupled peptide receptor (GPCR), substance K receptor, and also diverse members of both G protein-coupled metabotropic type and NMDA type of neurotransmitter glutamate receptors. We demonstrated many novel synaptic mechanisms involving distinct types of glutamate receptors in brain function and dysfunction. These include the mechanisms underlying segregation of light-dark signals in visual transmission, discrimination and memory formation in olfactory transmission, and motor co-ordination in the cerebellum, basal ganglia and the retinal network. 相似文献
15.
Svoboda P Teisinger J Novotný J Bourová L Drmota T Hejnová L Moravcová Z Lisý V Rudajev V Stöhr J Vokurková A Svandová I Durchánková D 《Physiological research / Academia Scientiarum Bohemoslovaca》2004,53(Z1):S141-S152
Many extracellular signals are at the cell surface received by specific receptors, which upon activation transduce information to the appropriate cellular effector molecules via trimeric G proteins. The G protein-mediated cascades ultimately lead to the highly refined regulation of systems such as sensory perception, cell growth, and hormonal regulation. Transmembrane signaling may be seriously deranged in various pathophysiological conditions. Over the last two decades the major experimental effort of our group has been devoted to better understanding the molecular mechanisms underlying transmembrane signaling regulated by G proteins and to the closely related process of desensitization of hormone response. This review provides general information about the basic principles of G protein-regulated transmembrane signaling as well as about our contribution to the current progress in the field. 相似文献
16.
Shpakov AO 《Zhurnal evoliutsionno? biokhimii i fiziologii》2007,43(1):3-23
The signal systems of the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, coupled to heterotrimeric G-proteins and sensitive to pheromones and alimentary molecules, are prototypes of hormonal signal systems of the higher vertebrate animals and are widely used in studies on molecular mechanisms of their functioning. This review summarizes and analyzes data on structural-functional organization of the first two components of these systems - receptors of the serpentine type and heterotrimeric G-proteins; mechanisms of functional coupling of receptors and G-proteins both between each other and to other signal proteins are discussed. It has been shown that at the early stages of evolution of signal systems, at the yeast level, various models of transduction of signals into the cell were tested; many of them differ essentially from the classic model of the three-component, G-protein-coupled signal system of the higher vertebrates. 相似文献
17.
Shpakov AO 《Tsitologiia》2002,44(3):242-258
In the review, data of the literature and own results on the functional coupling between the serpentine type receptors and the heterotrimeric G-proteins are analyzed and summarized. The role of cytoplasmic loops and C-tail domain of the receptors in interaction with G-protein alpha-subunits of different types is discussed. On the basis of theoretical analysis it is shown that the second cytoplasmic loop and the proximal to the membrane segments of the third cytoplasmic loop, containing the main G-protein-coupled molecular determinants, have the cationic nature and can form the helical structures. A molecular model of signal transduction from the receptor to G-protein, based on the electrostatic interactions between the cytoplasmic loops of receptors and receptor-binding regions of G-proteins, is developed. 相似文献
18.
The number of neuropeptides and their corresponding receptors has increased steadily over the last fourty years: initially, peptides were isolated from gut or brain (e.g., Substance P, somatostatin), then by targeted mining in specific regions (e.g., cortistatin, orexin in the brain), or by deorphanization of G‐protein‐coupled receptors (GPCRs; orexin, ghrelin receptors) and through the completion the Human Genome Project. Neuropeptides (and their receptors) have regionally restricted distributions in the central and peripheral nervous system. The neuropeptide signaling is somewhat more distinct spatially than signaling with classical, low‐molecular‐weight neurotransmitters that are more widely expressed, and, therefore, one assumes that drugs acting at neuropeptide receptors may have more selective pharmacological actions with possibly fewer side effects than drugs acting on glutamatergic, GABAergic, monoaminergic, or cholinergic systems. Neuropeptide receptors, which may have a few or multiple subtypes and splice variants, belong almost exclusively to the GPCR family also known as seven‐transmembrane receptors (7TM), a favorite class of drug targets in the pharmaceutical industry. Most neuropeptides are co‐stored and co‐released with classic neurotransmitters, albeit often only at higher frequencies of stimulation or at bursting activity, thus restricting the neuropeptide signaling to specific circumstances, another reason to assume that neuropeptide drug mimics may have less side effects. Neuropeptides possess a wide spectrum of functions from neurohormone, neurotransmitter to growth factor, but also as key inflammatory mediators. Neuropeptides become ‘active’ when the nervous system is challenged, e.g., by stress, injury, drug abuse, or neuropsychiatric disorders with genetic, epigenetic, and/or environmental components. The unsuspected number of true neuropeptides and their cognate receptors provides opportunities to identify novel targets for the treatment of both central and peripheral nervous system disorders. Both, receptor subtype‐selective antagonists and agonists are being developed, as illustrated by the success of somatostatin agonists, angiotensin, and endothelin antagonists, and the expected clinical applications of NK‐1/2/3 (substance P) receptor antagonists, CRF, vasopressin, NPY, neurotensin, orexin antagonists, or neuropeptide receptor modulators; such ligands have efficacy in preclinical or clinical models of pain and neuropsychiatric diseases, such as migraine, chronic/neuropathic pain, anxiety, sleep disorders, depression, and schizophrenia. In addition, both positive and negative allosteric modulators have been described with interesting in vivo activities (e.g., at galanin receptors). The field has become more complex now that an increasing number of heteromeric neuropeptide receptors are described, e.g., ghrelin receptors with 5‐HT2C or dopamine D1, D2 receptors. At long last, structure‐based drug discovery can now be envisaged with confidence, since crystal or solution structure of GPCRs and GPCR? ligand complexes, including peptide receptors, are published almost on a monthly basis. Finally, although most compounds acting at peptide receptors are still peptidomimetics, the last decade has seen the emergence of low‐molecular‐weight nonpeptide ligands (e.g., for orexin, ghrelin, or neurokinin receptors), and surprising progress has been made with β‐ and γ‐peptides as very stable and potent mimetics of, e.g., somatostatin (SRIF), where the native SRIF has a half‐life limited to 2–3 min. This last point will be illustrated more specifically, as we have had a long‐standing collaboration with Prof. D. Seebach to whom this review is dedicated at the occasion of his 75th birthday. 相似文献
19.
There are five subtypes of muscarinic acetylcholine receptors (M(1) to M(5)) which control a large number of physiological processes, such as the function of heart and smooth muscles, glandular secretion, release of neurotransmitters, gene expression and cognitive functions as learning and memory. A selective ligand is very useful for studying the function of a subtype in presence of other subtypes, which is the most common situation, since a cell or an organ usually has several subtypes. There are many non-selective muscarinic ligands, but only few selective ones. Mambas, African snakes of genus Dendroaspis have toxins, muscarinic toxins, that are selective for M(1), M(2) and M(4) receptors. They consist of 63-66 amino acids and four disulfides which form four loops. They are members of a large group of snake toxins, three-finger toxins; three loops are extended like the middle fingers of a hand and the disulfides and the shortest loop are in the palm of the hand. Some of the toxins target the allosteric site which is located in a cleft of the receptor molecule close to its extracellular part. A possible explanation to the good selectivity is that the toxins bind to the allosteric site, but because of their size they probably also bind to extracellular parts of the receptors which are rather different in the various subtypes. Some other allosteric ligands also have good selectivity, the alkaloid brucine and derivatives are selective for M(1), M(3) and M(4) receptors. Muscarinic toxins have been used in several types of experiments. For instance radioactively labeled M(1) and M(4) selective toxins were used in autoradiography of hippocampus from Alzheimer patients. One significant change in the receptor content was detected in one region of the hippocampus, dentate gyrus, where M(4) receptors were reduced by 50% in patients as compared to age-matched controls. Hippocampus is essential for memory consolidation. M(4) receptors in dentate gyrus may play a role, since they decreased in Alzheimers disease which destroys the memory. Another indication of the role of M(4) receptors for memory is that injection of the M(4) selective antagonist muscarinic toxin 3 (M(4)-toxin 1) into rat hippocampus produced amnesia. 相似文献
20.
Shvartsman SY Hagan MP Yacoub A Dent P Wiley HS Lauffenburger DA 《American journal of physiology. Cell physiology》2002,282(3):C545-C559
We describe a mechanism for context-dependent cell signaling mediated by autocrine loops with positive feedback. We demonstrate that the composition of the extracellular medium can critically influence the intracellular signaling dynamics induced by extracellular stimuli. Specifically, in the epidermal growth factor receptor (EGFR) system, amplitude and duration of mitogen-activated protein kinase (MAPK) activation are modulated by the positive-feedback loop formed by the EGFR, the Ras-MAPK signaling pathway, and a ligand-releasing protease. The signaling response to a transient input is short-lived when most of the released ligand is lost to the cellular microenvironment by diffusion and/or interaction with an extracellular ligand-binding component. In contrast, the response is prolonged or persistent in a cell that is efficient in recapturing the endogenous ligand. To study functional capabilities of autocrine loops, we have developed a mathematical model that accounts for ligand release, transport, binding, and intracellular signaling. We find that context-dependent signaling arises as a result of dynamic interaction between the parts of an autocrine loop. Using the model, we can directly interpret experimental observations on context-dependent responses of autocrine cells to ionizing radiation. In human carcinoma cells, MAPK signaling patterns induced by a short pulse of ionizing radiation can be transient or sustained, depending on cell type and composition of the extracellular medium. On the basis of our model, we propose that autocrine loops in this, and potentially other, growth factor and cytokine systems may serve as modules for context-dependent cell signaling. 相似文献