Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:56-45-1 (serine)
 65,846 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rho kinases (ROCKs), the first Rho effectors to be described, are serine/threonine kinases that are important in fundamental processes of cell migration, cell proliferation and cell survival. Abnormal activation of the Rho/ROCK pathway has been observed in various disorders of the central nervous system. Injury to the adult vertebrate brain and spinal cord activates ROCKs, thereby inhibiting neurite growth and sprouting. Inhibition of ROCKs results in accelerated regeneration and enhanced functional recovery after spinal-cord injury in mammals, and inhibition of the Rho/ROCK pathway has also proved to be efficacious in animal models of stroke, inflammatory and demyelinating diseases, Alzheimer's disease and neuropathic pain. ROCK inhibitors therefore have potential for preventing neurodegeneration and stimulating neuroregeneration in various neurological disorders.
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PMID:Rho kinase, a promising drug target for neurological disorders. 1586 68

Accumulated evidence implicates the anterior cingulate cortex (ACC) in pain processing. The activation of the NMDA receptor requires the occupation of both the glutamate site and the glycine site. d-Serine released by astrocytes is presumed to be an endogenous ligand for the glycine site of the NMDA receptor. Using whole-cell patch clamp recording, membrane characteristics and effects of exogenous d-serine on NMDA-evoked currents were examined in neurons in ACC slices from normal and complete Freund's adjuvant-induced monoarthritic rats. Neurons from rats with monoarthritis exhibited more depolarized membrane potential, lower firing threshold, lower input resistance and higher slope conductance compared with normal rats. The NMDA-evoked currents were enhanced by d-serine (20 microM) in both normal (135.3+/-4.3% of control, p < 0.01) and arthritic (157.9 +/- 9.7% of control, p < 0.01) rats, respectively. The effect of d-serine was greater in arthritic rats than control rats (p < 0.05). These results suggest that inflammatory pain increased the excitability of ACC neurons, and that the NMDA receptor glycine sites in the ACC neurons were not saturated in either normal or inflammatory pain states.
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PMID:Alterations of membrane properties and effects of D-serine on NMDA-induced current in rat anterior cingulate cortex neurons after monoarthritis. 1591 54

Protease-activated receptors (PARs), a family of G-protein-coupled seven-transmembrane-domain receptors, are activated by proteolytic unmasking of the N-terminal cryptic tethered ligand by certain serine proteases. Among four PAR family members cloned to date, PAR-1, PAR-2, and PAR-4 can also be activated through a non-enzymatic mechanism, which is achieved by direct binding of exogenously applied synthetic peptides based on the tethered ligand sequence, known as PARs-activating peptides, to the body of the receptor. Various peptide mimetics have been synthesized as agonists for PARs with improved potency, selectivity, and stability. Some peptide mimetics and/or nonpeptide compounds have also been developed as antagonists for PAR-1 and PAR-4. PARs are widely distributed in the mammalian body, especially throughout the alimentary systems, and play various roles in physiological/pathophysiological conditions, i.e., modulation of salivary, gastric, or pancreatic glandular exocrine secretion, gastrointestinal smooth muscle motility, gastric mucosal cytoprotection, suppression/facilitation of visceral pain and inflammation, etc. Thus PARs are now considered novel therapeutic targets, and development of selective agonists and/or antagonists for PARs might provide a novel strategy for the treatment of various diseases that are resistant to current therapeutics.
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PMID:[Development of agonists/antagonists for protease-activated receptors (PARs) and the possible therapeutic application to gastrointestinal diseases]. 1593 Aug 17

Certain serine proteases from the circulation (e.g., coagulation factors), inflammatory cells (e.g., mast-cell tryptase, neutrophil proteinase 3), and from many other cell types (e.g., trypsins) can specifically signal to cells by cleaving protease-activated receptors (PARs), a family of four G protein-coupled receptors. Proteases cleave PARs at specific sites within the extracellular amino-terminus to expose amino-terminal tethered ligand domains that bind to and activate the cleaved receptors. The proteases that activate PARs are often generated and released during injury and inflammation, and activated PARs orchestrate tissue responses to injury, including hemostasis, inflammation, pain, and repair. This review concerns protease and PAR signaling in the nervous system. Neurons of the central and peripheral nervous systems express all four PARs. Proteases that may derive from the circulation, inflammatory cells, or neural tissues can cleave PARs on neurons and thereby activate diverse signaling pathways that control survival, morphology, release of neurotransmitters, and activity of ion channels. In this manner proteases and PARs regulate neurodegeneration, neurogenic inflammation, and pain transmission. Thus, PARs may participate in disease states and PAR antagonists or agonists may be useful therapies for certain disorders.
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PMID:Protease-activated receptors: regulation of neuronal function. 1605 40

Proteinases like thrombin and trypsin, long known for their ability to activate the coagulation cascade or to act as hormone-processing enzymes, are now recognised as hormone-like regulators of cell function. These serine proteinases activate cell signalling by triggering a novel four-member family of G-protein-coupled receptors, termed Proteinase-Activated Receptors (PARs). This review article summarises historically the discovery of PARs as well as their unique mechanism of activation and outlines a number of different pathophysiological settings in which PARs can act to regulate cell and tissue function. PARs can be seen to play a role in pathophysiological processes ranging from inflammation and pain to cardiovascular disease and cancer. Apart from activating PARs to cause their physiological effects in tissues, proteinases can also mediate cell signalling via a number of other mechanisms, including the activation of growth factor receptors, like the one for insulin. Therefore, this article also describes the non-PAR mechanisms whereby proteinases can have hormone-like actions in cells and tissues.
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PMID:Proteinases as hormone-like signal messengers. 1620 79

A comparative study of neotropic activity of semax (MEHFPGP), an analogue of the ACTH(4-10), and some of its derivatives in which the N-terminal methionine was modified or substituted with other amino acid residues was performed. The effect of these peptides on learning of albino rats in tests with positive (alimentary) and negative (pain) reinforcement was studied. In the case of modification of methionine by attachment of the gluconic-acid residue or substitution of methionine with lysine, the neotropic effect of the peptide was retained. The substitution of methionine with tryptophan or serine resulted in a decrease in the neotropic activity. The substitution of methionine with glycine, threonine, or alanine caused a complete loss of the neotropic activity of the peptide. Therefore, the amino acid residue located at position 1 of the heptapeptide analogue semax, plays a key role in retaining the neotropic effects of the peptide and determines the degree of their expression.
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PMID:[Effect of modification of the N-terminal region of molecule on the expression of neotropic effect of semax analogues]. 1621 68

Mu-conotoxin SIIIA, a novel blocker of tetrodotoxin-resistant (TTX-R) voltage-gated sodium channels (VGSCs) has been identified from the fish-hunting cone snail, Conus striatus. The deduced sequence consists of a 20-residue signal peptide, a 31-residue pro-peptide, and a 20-residue mature toxin with its N-terminal Gln cyclized and C-terminus amidated. Mu-SIIIA shares the common cysteine arrangement with other mu-conotoxins. Besides, it exhibits high sequence homology with mu-SmIIIA, a toxin recently characterized from C. stercusmuscarum which potently blocks the TTX-R VGSCs in frog neurons. With whole-cell recording, mu-SIIIA potently and selectively inhibits the TTX-R VGSCs of dissociated adult rat small-diameter dorsal root ganglia (DRG) neurons with a dose- and time-dependent property and irreversibly. Homology-based modeling of mu-PIIIA, SIIIA and SmIIIA implies that they share a common backbone conformation except at the N termini. The hydroxyl-proline residue only present in mu-PIIIA is absent and substituted by an Asp residue in mu-SIIIA and SmIIIA. Similarly, one crucial basic residue (Arg12 in mu-PIIIA) is replaced by serine in the latter two toxins. Such differences might endow them with the capacity to selectively inhibit TTX-S or TTX-R VGSCs. Considering that TTX-R VGSCs predominantly expressed in DRG neurons play pivotal roles in the nociceptive information transmission and that their specific antagonists are still lacking, mu-SIIIA might provide a useful tool for functional studies of these channels, and potentially be developed as an efficient pain killer.
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PMID:A novel conotoxin from Conus striatus, mu-SIIIA, selectively blocking rat tetrodotoxin-resistant sodium channels. 1632 17

Single unit extracellular recordings from dorsal horn neurons were performed with glass micropipettes in pentobarbital-anesthetized rats. A total of 60 wide dynamic range (WDR) neurons were obtained from 34 rats. In normal rats (20/34), spinally administered D-serine (10 nmol), a putative endogenous agonist of glycine site of NMDA receptors, significantly enhanced the C- but not Abeta-, and Adelta-fiber responses of WDR neurons in the spinal dorsal horn. When 1 nmol of the glycine site antagonist 7-chlorokynurenic acid (7-CK) was co-administered with 10 nmol D-serine, the facilitation of D-serine on C-fiber response was completely blocked. 7-CK (1 nmol) alone failed to influence Abeta-, Adelta-, and C-fiber responses of WDR neurons. In contrast, in carrageenan-injected rats (14/34), 10 nmol D-serine had no effect on C-fiber response, while 1 nmol 7-CK per se markedly depressed C-fiber response of WDR neurons. These findings suggest that under physiological conditions, glycine sites in the spinal cord were available but became saturated following peripheral inflammation. Thus, increased endogenous d-serine or glycine may be involved in nociceptive transmission by modulating NMDA receptor activities. The glycine site of NMDA receptors may become a target for the prevention of inflammatory pain.
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PMID:Distinct effects of D-serine on spinal nociceptive responses in normal and carrageenan-injected rats. 1654 23

Certain serine proteases that originate from the circulation (coagulation factors), inflammatory cells (mast cell tryptase, neutrophil granzyme A, and proteinase 3), and epithelial and neuronal tissues (trypsins) can specifically regulate cells by cleaving protease-activated receptors (PARs), a family of four G-protein-coupled receptors. Proteases cleave PARs on multiple cell types to reveal tethered ligand domains that bind to and activate the cleaved receptors. The proteases that activate PARs are often generated and secreted during injury and inflammation, and PARs orchestrate tissue responses to these insults, including hemostasis, inflammation, nociception, and repair mechanisms. Agonists of PARs, notably PAR2, induce inflammation in many tissues that is characterized by hyperemia, extravasation of plasma proteins, granulocyte infiltration, and alterations in epithelial permeability. These effects are mediated in part by the release of neuropeptides substance P and calcitonin gene-related peptide from sensory nerve fibers in peripheral tissues. Proteases that activate PAR2 also induce the release of neuropeptides from the central projections of these nerves in the dorsal horn of the spinal cord, where they participate in pain transmission. Accumulating evidence from PAR-deficient mice indicates that these mechanisms may contribute to experimental models of disease and raise the possibility that protease inhibitors and PAR antagonists may be useful therapies for a variety of inflammatory and painful conditions.
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PMID:Protease-activated receptors: how proteases signal to cells to cause inflammation and pain. 1667 65

Although previous reports have suggested that the sigma 1 (sigma(1)) receptor may be involved in pain sensation, its specific site of action has not been elucidated. The aim of present study was to determine the role of the spinal sigma(1) receptor in formalin-induced pain behavior, spinal cord Fos expression and phosphorylation of N-methyl-D-aspartate receptor subunit 1 (pNR1). Intrathecal (i.t.) pretreatment with the selective sigma(1) receptor antagonist, BD-1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide) (10-100 nmol) dose dependently reduced formalin-induced pain behaviors in second phase, but not first phase, of the formalin test. I.t. injection of BD-1047 also reduced formalin-evoked Fos expression and pNR1 at the protein kinase C-dependent site, serine-896 (Ser896) and the protein kinase A-dependent site, serine-897 (Ser897) in spinal dorsal horn.i.t. BMY-14802 ((alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol hydrochloride) (10-100 nmol, sigma(1) receptor antagonist and 5-HT(1A) receptor agonist) dose dependently reduced formalin-induced pain behaviors in both phases. However, the 5-HT(1A) receptor might not be involved in the antinociceptive effect of BMY-14802 on the second phase, since i.t. pretreatment with the 5-HT(1A) receptor antagonist propranolol ((S)-1-isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride) (injected 10 min prior to i.t. BMY-14802) partially blocked the effect of BMY-14802 on the first phase of the formalin test but did not affect the inhibitory effect of BMY-14802 on the second phase. In addition, i.t. BMY-14802 significantly reduced formalin-evoked Fos expression and pNR1 (Ser896 and Ser897) expression in spinal dorsal horn. The results of this study suggest that selective blockage of spinal sigma(1) receptors can reduce pain behaviors, spinal cord Fos expression and pNR1 (Ser896 and Ser897) expression associated with the second phase of the formalin test.
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PMID:Intrathecal treatment with sigma1 receptor antagonists reduces formalin-induced phosphorylation of NMDA receptor subunit 1 and the second phase of formalin test in mice. 1668 60


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