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)

Bothrops jararaca venom (Bjv) is known to induce local inflammation and severe pain. Since, mast cells are able to secrete mediators involved in algesic processes, in this study we examined the putative role of these cells in the hyperalgesia triggered by Bjv in the rat paw. We noted that treatment with mast cell stabilizer sodium cromoglicate as well as with histamine and 5-hydroxytriptamine receptor antagonists meclizine and methysergide, respectively, inhibited the Bjv-induced hyperalgesia. In addition, we showed that stimulation of isolated rat peritoneal mast cells with Bjv in vitro resulted in the release of stored and neo-generated inflammatory mediators such as histamine and leukotriene C(4), respectively. Bjv-induced histamine secretion was clearly sensitive to treatment with sodium cromoglicate and sodium nedocromil. We further observed that metalloproteinase inhibitors 1,10-phenantroline and DM43 inhibited mast cell degranulation in vitro, under conditions where inhibitors of phospholipase A(2) as well as of serine- and cysteine-proteinases were inactive. Altogether, our findings indicate that mast cells seem to contribute to the hyperalgesia caused by Bjv in the rat paw, and also provide evidence that this response might be dependent on the ability of the Bjv to activate directly mast cells.
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PMID:Contribution of mast cells and snake venom metalloproteinases to the hyperalgesia induced by Bothrops jararaca venom in rats. 1673 41

The transient receptor potential (TRP) channels are a group of Ca2+-permeable cation channels (except TRPM4 and TRPM5) that function as cellular sensors of various internal and external stimuli. Most of these channels are expressed in the nervous system and they play a key role in sensory physiology. They may respond to temperature, pressure, inflammatory agents, pain, osmolarity, taste and many other stimuli. Recent development indicates that the activity of these channels is regulated by protein phosphorylation and dephosphorylation of serine, threonine, and tyrosine residues. In this review, we present a comprehensive summary of the literature regarding the TRP channel regulation by different protein kinases.
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PMID:Regulation of TRP channels by phosphorylation. 1677 30

Temporomandibular joint (TMJ) disorders are painful conditions that are more prevalent in women than men. This study tested the hypothesis that acute inflammation of the TMJ region evoked sex-related changes in amino acid transmitter concentrations at the trigeminal subnucleus/upper cervical cord (Vc/C2) junction, the major terminal zone for TMJ sensory afferents. Microdialysis samples were collected in male, intact and ovariectomized (OvX) female rats after injection of mustard oil into the TMJ region (TMJ-MO) under barbiturate anesthesia. Males displayed increases in glutamate, aspartate and serine at 5 min and secondary increases 40-45 min after TMJ-MO. Intact and OvX females given low dose estrogen (LE2) displayed increases in glutamate, aspartate and serine at 5 min but no secondary increase at 40 min, while OvX females given high dose estrogen (HE2) revealed no increases after TMJ-MO. Glycine increased 20 min after TMJ-MO in males and cycling females, but not in OvX rats. Perfusion of high potassium through the probe evoked similar increases in glutamate, aspartate and glycine in all groups. In separate experiments, perfusion of the glutamate-aspartate reuptake inhibitor, L-trans-2,4-pyrrolidine dicarboxylate (PDC), through the probe caused a prompt elevation in glutamate that was significantly greater in HE2 than LE2 females or males. These results suggested sex hormone status affects glutamatergic neurotransmission at the Vc/C2 junction by acting, in part, through modulation of glutamate reuptake. Altered amino acid transmitter release and/or availability at the Vc/C2 junction may contribute to differential processing of sensory input from the TMJ region in males and females.
Pain 2006 Dec 15
PMID:Amino acid release at the spinomedullary junction after inflammation of the TMJ region in male and female rats. 1690 47

N-Methyl-d-aspartic acid (NMDA) receptors are known to function in the mediation of pain and have a significant role in the development of hyperalgesia following inflammation. Serine phosphorylation regulation of NMDA receptor function occurs in a variety of conditions. No studies have demonstrated a change in phosphorylation of enteric NMDA receptors following colonic inflammation. We examined the levels of NMDA NR1 phosphorylation in trinitrobenzene sulfonic acid (TNBS) induced colitis in rats and compared it to protein translation and the development of visceral hypersensitivity. We have previously, demonstrated an increase in the C1 cassette of NR1 mRNA expression at 14, 21, and 28 days following TNBS administration. In this study, we examined the NR1 serine phosphorylation at 14 days following TNBS injection. Male Sprague-Dawley rats (200-250 g) were treated with TNBS (20mg per rat) diluted in 50% ethanol (n=3) and vehicle controls of 50% ethanol (n=3). TNBS and vehicle controls were administered with a 24 gauge catheter inserted into the lumen of the rat colon. The animals were sacrificed at 14 days after induction of the colitis and their distal colon was retrieved for two-dimensional (2D) western blot analysis. Serine phosphorylation of the NR1 subunit with C1 cassette appears at 14 days after TNBS injection. In contrast, there was no NR1-C1 expression in the vehicle controls and untreated normal controls. These results suggest a role for colonic-NMDA receptor phosphorylation in the development of neuronal plasticity following colonic inflammation. Phosphorylation of NR1 may partially explain visceral hypersensitivity present during colonic inflammation.
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PMID:Phosphorylation of NMDA NR1 subunits in the myenteric plexus during TNBS induced colitis. 1694 39

Inhibitors of the enzyme fatty acid amide hydrolase (FAAH), the principal enzyme involved in the metabolism of the endogenous cannabinoid anandamide, have potential utility in the treatment of disorders including inflammation and inflammatory pain. The carbamate compound URB597 (3'-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate) potently and selectively inhibits FAAH by forming a covalent bond with a key serine residue of the enzyme. Little is known as to the pH dependency of this inhibition. Using a preincubation time of 10min, URB597 inhibited rat brain anandamide hydrolysis with pI(50) values of 7.19+/-0.02 and 7.75+/-0.06 at pH 6 and 8, respectively. The inhibition was time-dependent, and second order rate constants of approximately 0.15x10(6)M(-1)min(-1) (pH 6) and approximately 1.2x10(6)M(-1)min(-1) (pH 8) could be estimated. In intact C6 glioma cells and using a preincubation time of 10min, URB597 inhibited the hydrolysis of 250nM [(3)H]AEA hydrolysis with pI(50) values of 5.58+/-0.07 and 6.45+/-0.07 at extracellular pH values of 6 and 8, respectively. Since tissue pH is affected by inflammation, these data would suggest that the pH selectivity of the inhibition can contribute to the potency of the compound in vivo.
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PMID:The potency of the fatty acid amide hydrolase inhibitor URB597 is dependent upon the assay pH. 1699 68

The Nav1.7 sodium channel is preferentially expressed in most nociceptive dorsal root ganglion neurons and in sympathetic neurons. Inherited erythromelalgia (IEM, also known as erythermalgia), an autosomal dominant neuropathy characterized by burning pain in the extremities in response to mild warmth, has been linked to mutations in Nav1.7. Recently, a substitution of Ser-241 by threonine (S241T) in the domain I S4-S5 linker of Nav1.7 was identified in a family with IEM. To investigate the possible causative role of this mutation in the pathophysiology of IEM, we used whole-cell voltage-clamp analysis to study the effects of S241T on Nav1.7 gating in HEK293 cells. We found a hyperpolarizing shift of activation midpoint by 8.4 mV, an accelerated time to peak, slowing of deactivation, and an increase in the current in response to small, slow depolarizations. Additionally, S241T produced an enhancement of slow inactivation, shifting the midpoint by -12.3 mV. Because serine and threonine have similar biochemical properties, the S241T substitution suggested that the size of the side chain at this position affected channel gating. To test this hypothesis, we investigated the effect of S241A and S241L substitutions on the gating properties of Nav1.7. Although S241A did not alter the properties of the channel, S241L mimicked the effects of S241T. We conclude that the linker between S4 and S5 in domain I of Nav1.7 modulates gating of this channel, and that a larger side chain at position 241 interferes with its gating mechanisms.
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PMID:Size matters: Erythromelalgia mutation S241T in Nav1.7 alters channel gating. 1700 10

Fatty acid amide hydrolase (FAAH) is the primary regulator of several bioactive lipid amides including anandamide. Inhibitors of FAAH are potentially useful for the treatment of pain, anxiety, depression, and other nervous system disorders. However, FAAH inhibitors must display selectivity for this enzyme relative to the numerous other serine hydrolases present in the human proteome in order to be therapeutically acceptable. Here we employed activity-based protein profiling (ABPP) to assess the selectivity of FAAH inhibitors in multiple rat and human tissues. We discovered that some inhibitors, including carbamate compounds SA-47 and SA-72, and AM404 are exceptionally selective while others, like URB597, BMS-1, OL-135, and LY2077855 are less selective, displaying multiple off-targets. Since proteins around 60kDa constitute the major off-targets for URB597 and several other FAAH inhibitors with different chemical structures, we employed the multi-dimensional protein identification technology (MudPIT) approach to analyze their identities. We identified multiple carboxylesterase isozymes as bona fide off-targets of FAAH inhibitors. Consistently, enzymatic assay confirmed inhibition of carboxylesterase activities in rat liver by FAAH inhibitors. Since carboxylesterases hydrolyze a variety of ester-containing drugs and prodrugs, we speculate that certain FAAH inhibitors, by inhibiting carboxylesterases, might have drug-drug interactions with other medicines if developed as therapeutic agents.
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PMID:Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets. 1721 69

The roles of serine proteases and protease activated receptors have been extensively studied in coagulation, wound healing, inflammation, and neurodegeneration. More recently, serine proteases have been suggested to influence synaptic plasticity. In this context, we examined the role of protease activated receptor 1 (PAR1), which is activated following proteolytic cleavage by thrombin and plasmin, in emotionally motivated learning. We were particularly interested in PAR1 because its activation enhances the function of NMDA receptors, which are required for some forms of synaptic plasticity. We examined several baseline behavioral measures, including locomotor activity, expression of anxiety-like behavior, motor task acquisition, nociceptive responses, and startle responses in C57Bl/6 mice in which the PAR1 receptor has been genetically deleted. In addition, we evaluated learning and memory in these mice using two memory tasks, passive avoidance and cued fear-conditioning. Whereas locomotion, pain response, startle, and measures of baseline anxiety were largely unaffected by PAR1 removal, PAR1-/- animals showed significant deficits in a passive avoidance task and in cued fear conditioning. These data suggest that PAR1 may play an important role in emotionally motivated learning.
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PMID:Learning and memory deficits in mice lacking protease activated receptor-1. 1754 3

D-Serine has recently been identified as a major gliotransmitter in the mammal central nervous system (CNS). The distribution of D-serine is analogous to the N-methyl-D-aspartate (NMDA)-type glutamate receptors in the brain. D-Serine is as potent as glycine as a coagonist at the glycine-binding site of NMDA receptors. Thus, D-serine has been considered as an endogenous ligand of the NMDA receptors in the brain. D-Serine is synthesized by serine racemase (SR) from L-serine. Both D-serine and SR have been enriched to astrocytes which are the dynamic partners of neurons at synapses and participate in controlling synaptic transmission, synaptic plasticity and synaptogenesis. The present review highlights the most recent findings on the molecular mechanisms of controlling D-serine metabolism in the CNS, the physiological role of D-serine in synaptic plasticity, and the pathological relevance of D-serine to schizophrenia, excitotoxicity- and neuroinflammation-induced neuronal death as well as neuropathic pain. Finally, as we have recently established SR knockout mouse strain with pure C57BL/6 genetic background, this novel mouse model will contribute the analysis of physiological and pathophysiological role of D-serine in vivo.
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PMID:[Role of D-serine in the mammalian brain]. 1766 43

Proteinase-activated receptors (PARs) are a family of G-protein-coupled receptors that are activated by endogenous serine proteinases that cleave the N-terminal domain of the receptor unmasking a "tethered ligand" sequence. Trypsin and other agonists at PAR(2) act on peripheral nerves to augment the transfer of nociceptive information. We tested whether PAR(2) agonists also exert a spinal pronociceptive effect by i.t. administering the selective ligand, Ser-Leu-Ile-Gly-Arg-Leu-NH(2) (SLI-GRL). This produced thermal and mechanical hyperalgesia in rats and mice and augmented mechanical and thermal hyperalgesia seen in the formalin inflammatory pain test. Effects of SLIGRL were abrogated in PAR(2)-deficient mice and were not seen with the inactive control peptide, Leu-Arg-Gly-Ile-Leu-Ser-NH(2). Surprisingly, electrophysiological studies, using whole-cell recording from rat substantia gelatinosa neurons, failed to demonstrate an increase in excitatory transmission or neuronal excitability following treatment with SLIGRL or trypsin. In fact, the actions of trypsin were consistent with a decrease in dorsal horn excitability. SLIGRL and trypsin did, however, depolarize and increase the excitability of large, medium and small primary afferent, dorsal root ganglion neurons. The effects were associated with an increase in conductance at hyperpolarized potentials and a decrease in conductance at depolarized potentials. PAR(2)-like immunoreactivity was found in DRG but not in spinal dorsal horn. These results suggest that activation of DRG neuron cell bodies may account for the pronociceptive actions of i.t. applied PAR(2) agonists. They also imply that pathophysiological release of PAR(2)-activating proteases in the vicinity of DRG neurons may produce profound effects on nociceptive processing in vivo.
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PMID:Intrathecal administration of proteinase-activated receptor-2 agonists produces hyperalgesia by exciting the cell bodies of primary sensory neurons. 1792 Nov 88


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