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)

Substance P binds to and activates the neurokinin-1 receptor with high affinity, thereby modulating several neuronal pathways including pain transmission and neurogenic inflammation. Several high affinity non-peptide antagonists have recently been described. To elucidate the molecular interactions specific for binding to the neurokinin-1 receptor, site-directed mutagenesis has been utilized to identify amino acid residues that interact directly with antagonists. Glutamine 165 in the fourth transmembrane segment was shown to be critical for the binding of CP-96,345 but not SR140333. Analysis of quinuclidine analogs suggests that glutamine 165 interacts with the C-3 heteroatom in this class of antagonists, probably through a hydrogen bond. Glutamine 165 also plays a minor role in the binding of peptides and RP67580. In contrast, serine 169 was determined to be critical for the binding of RP67580. These data indicate that residues 165 and 169 in the fourth transmembrane segment, along with residues in the fifth, sixth, and seventh transmembrane segments as demonstrated previously, form the non-peptide antagonist binding site in the neurokinin-1 receptor. Furthermore, the antagonist binding site overlaps with the binding site for peptide agonists in the fourth and seventh transmembrane segments.
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PMID:Interaction of glutamine 165 in the fourth transmembrane segment of the human neurokinin-1 receptor with quinuclidine antagonists. 819 29

A 28-year-old man had complaints of muscle weakness in both his legs and fingers. Moderate degrees of symmetrical atrophy adn weakness of the bilateral lower limbs, moderate degree of muscle atrophy was also noticed distal to the lower one third of the upper thigh. A moderate degree of weakness of the anterior tibial, extensor digitorum and peroneus muscles was also noted. Pes cavus deformity was evident bilaterally. Knee jerk was normal, and Achilles tendon reflex was absent without pathologic reflexes. He could not walk on his heels. Vibratory sensation was severely decreased in the toes, and both touch and pain sensations were slightly decreased on the dorsum of the feet. The median motor nerve conduction velocity was 28.9 m/sec with a prolonged distal latency. An amplitude of M-wave evoked by electrical stimulation of the median nerve 1 mV. No M-wave was obtained from stimulation of the tibial nerve, and no sensory nerve action potentials were elicited from electrical stimulation of the median and sural nerves. Histologic studies of the biopsied sural nerve revealed the occasional presence of internodes with a thin myelin sheath and a decrease in the density of large myelinated fibers. Small and atypical onion-bulbs were occasionally observed by electron microscopy. Based on the neurological examination and nerve conduction study of the family members, a sister, mother and grandmother of the proband were found to be mildly affected without any disability in their daily activities. However, the father and an uncle on the mother's side of the proband were normal. Therefore, we concluded clinically that this family had HMSN type I with autosomal dominant inheritance or X-linked HMSN. In the studies of fluorescence in situ hybridization and restriction fragment length polymorphism of the genomic DNA of the proband, a DNA duplication in chromosome 17p11.2-12 was not observed. A single-strand conformational polymorphism analysis of the genomic DNA encoding connexin32 (Cx32) revealed the abnormal band different from that of the control. A sequence analysis of the genomic DNA obtained by use of the polymerase chain reaction was also performed. It revealed that there was a mutant allele, a cytosine to thymine substitution of the nucleotide position 140, which caused a substitution of leucine for serine at amino acid position 26. The proband's mother was heterozygous for the mutant allele and the normal allele. This type of Cx32 mutation was different from any type of Cx32 mutation reported in the literature. The mutation in this family is located in the first transmembrane portion of Cx32, and may alter the function of Cx32 protein, as well as lead to the functional and structural abnormalities of the myelin sheath at the nodes of Ranvier and Schmidt-Lanterman's incisures, where Cx32 is present. This is the first Japanese X-linked HMSN family showing a new type of mutation of Cx32 gene with clinical findings and a histologic evaluation of the sural nerve.
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PMID:[A family of X-linked motor and sensory neuropathy with a new type of connexin32 mutation]. 866 24

Inflammation of the temporomandibular joint (TMJ) region evokes pain and hyperalgesia as well as causing persistent changes in the response properties of central trigeminal neurons. To determine if excitatory amino acids have a role in TMJ-induced responses, extracellular concentrations were measured in microdialysate samples from probes positioned in the spinal trigeminal nucleus (Vsp) near the transition region between subnucleus interpolaris and subnucleus caudalis (Vi/Vc) in chloralose-anesthetized rats. Injection of the selective small fiber excitant, mustard oil (20 microliters, 20% solution), into the ipsilateral TMJ region caused a transient (by 10 min) increase in glutamate (from 0.48 +/- 0.16 to 1.94 +/- 0.78 microM, P < 0.005) and aspartate (from 0.29 +/- 0.11 to 1.78 +/- 0.82 microM, P < 0.025) among sites located at the ventrolateral pole of the Vi/Vc transition region (n = 6). Samples from probes located within the ventral Vsp, but outside this Vi/Vc transition region (n = 9), did not show significant changes in amino acid concentrations. Glutamate and aspartate also increased after mustard oil injections into the contralateral TMJ region. Dialysate concentrations of serine and taurine did not change significantly after mustard oil injections. Addition of high potassium (150 mM) to the perfusate solution caused increases in glutamate and aspartate regardless of probe location. The transient and selective release of glutamate and aspartate within the Vi/Vc transition after acute irritation of the TMJ region is consistent with a proposed role for excitatory amino acids in mediating noxious sensory input from deep orofacial structures. Together with previous reports of c-fos expression, these results suggest that neurons within the ventrolateral portion of the Vi/Vc transition may serve as a relay site for the integration of sensory or reflex responses to acute inflammation of the TMJ region.
Pain 1996 Oct
PMID:Excitatory amino release within spinal trigeminal nucleus after mustard oil injection into the temporomandibular joint region of the rat. 895 41

Tissue kallikrein is a serine proteinase which processes kininogens to release bioactive kinins. Kinins mediate a variety of biological processes through the interaction with kinin receptors. Kinins are involved in the regulation of blood pressure and local blood flow, vasodilation, smooth muscle contraction and relaxation, production of pain and inflammation, and stimulation of cell proliferation. The tissue kallikrein-kinin system has been implicated in a number of pathophysiological processes such as hypertension, allergy and diabetes mellitus. In the present study, we have identified the expression and localization of components of the kallikrein-kinin system in the human eye by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analyses, and in situ hybridization histochemistry. RT-PCR and Southern blot analyses have detected mRNAs of the key components of the system including tissue kallikrein, low molecular weight kininogen, and bradykinin B1 and B2 receptors at high levels in human retina, choroid and ciliary body, and relatively low levels in the optic nerve. In situ hybridization has identified cellular localization of these four mRNAs in ocular tissues. They are expressed in retinal neuronal cells including the outer nuclear layer, inner nuclear layer and ganglion cell layer. These mRNAs were also identified in endothelial cells of ocular blood vessels, ciliary muscle and lens epithelial cells. The sense riboprobes showed negative staining, which indicates the specificity of the antisense riboprobes. These results suggest that the tissue kallikrein-kinin system is produced endogenously in human ocular tissues. Similar expression patterns of kallikrein, kininogen and kinin receptors indicate that the kallikrein-kinin system may function in an autocrine or paracrine fashion in the eye.
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PMID:Expression and cellular localization of the kallikrein-kinin system in human ocular tissues. 898 60

The effect of the inositol trisphosphate analog alpha-trinositol on noxious-evoked behavior, amino acid and prostaglandin E2 (PGE2) release was examined in unanesthetized rats using intrathecal microdialysis probes. Subcutaneous injection of 50 microliters 5% formalin solution produced two phases of pain-like behavior and significant elevation of glutamate, aspartate, glycine, taurine and serine during phase 1. PGE2 concentrations were increased during both phases 1 and 2. Intraperitoneal delivery of 300 mg/kg alpha-trinositol significantly suppressed both phases 1 and 2 of formalin-induced behavior and the associated elevation of amino acids and PGE2. These data demonstrate that the antinociceptive effect of alpha-trinositol corresponds to suppression of noxious-evoked release of amino acids and PGE2 from the spinal cord.
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PMID:The effect of alpha-trinositol (D-myo-inositol 1,2,6-trisphosphate) on formalin-evoked spinal amino acid and prostaglandin E2 levels. 904 42

Voltage-gated tetrodotoxin (TTX)-resistant sodium channels present in primary sensory neurons may be responsible for the excitability of nociceptors, and may underlie pain and tenderness associated with tissue injury and inflammation. Here, we report the cloning of a putative sodium channel (NaNG) from dog nodose ganglia. The sequence of the full-length cDNA predicts an open reading frame of 5886 nucleotides encoding a protein of 1962 amino acids. The predicted protein shows 82.3% identity with the recently discovered TTX-resistant sodium channel (SNS/PN3). In the TTX-binding site, a serine appears as in TTX-resistant SNS/PN3, instead of Cys (as in TTX-insensitive cardiac channels) and Tyr/Phe (as in TTX-sensitive sodium channels). Coupled transcription and translation of full-length cDNA produced a 220-kDa protein; based on Northern blot and RT-PCR analysis, its expression is restricted to nodose ganglia, and not present in cortex, hippocampus, cerebellum, liver, heart or skeletal muscle. We propose that NaNG might be a new member of the TTX-resistant sodium channel family expressed in sensory neurons.
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PMID:Molecular cloning of a putative tetrodotoxin-resistant sodium channel from dog nodose ganglion neurons. 942 39

Degradation of synthetic human beta-endorphin by a human plasma proteinase was studied with high-performance liquid chromatography in combination with mass spectrometry. The peptide was metabolized at a rate of 25 pmol/min to the major fragments beta-endorphin (1-19) and (20-31), the latter reported as a potent inhibitor of morphine- and beta-endorphin-induced analgesia in mice. The proteinase responsible for this process was classified as a metal-dependent serine proteinase and was effectively inactivated by phenylmethylsulfonyl fluoride and ethylenediaminetetraacetic acid. Identification of the products formed during the enzymatic reaction was performed by liquid chromatography on-line with electrospray mass spectrometry, using a reversed-phase or a novel size-exclusion column capable of separating molecules between 0.1-7 kilodaltons. Peptide sequences were verified by tandem mass spectrometry experiments. The conversion of beta-endorphin may have physiological implications in the mechanism of pain. The obtained data suggest that several precautions should be considered during recovery and measurement of beta-endorphin in plasma by immunological techniques. The applied strategy may also be useful for studying metabolism of various peptidergic compounds with potential pharmacological significance.
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PMID:Metabolism of beta-endorphin in plasma studied by liquid chromatography-electrospray ionization mass spectrometry. 953 75

Gabapentin (GP) has been shown to have antihyperalgesic properties and the site of drug action is reported to be the central nervous system. The goal of the present study was to determine whether GP also has a peripheral site of action. Rats received intraplantar 20-microl injections of 6, 60 or 600 microg GP + 2% formalin, 300 or 600 microg S-(+)-3-isobutylgaba + 2% formalin, 600 microg R-(-)-3-isobutylgaba + 2% formalin or formalin alone. The two lower doses of GP significantly reduced flinching and lifting/licking behavior during phase 2; however, phase 1 behaviors were unaffected, 600 microg GP significantly reduced these nociceptive behaviors during both phases. 600 microg S-(+)-3-isobutylgaba also reduced formalin-induced nociceptive behaviors; however, 600 microg of the isomer R-(-)-3-isobutylgaba had no effect. The antihyperalgesic effect of GP (1) was not due to a systemic effect since animals injected with 600 microg GP in one hindpaw and 2% formalin into the contralateral hindpaw developed nociceptive behaviors which were no different than those seen in animals injected with formalin alone; (2) was not due to a local anesthetic effect since needle sticks within the drug-injected region evoked paw withdrawal behavior which was not different from pre-drug levels; (3) was blocked by 20 microl D-serine but not by L-serine. Although the mechanism of action of GP has yet to be elucidated, these results indicate that GP has a peripheral site of action and thus may offer a novel therapeutic agent for topical or local treatment of pain of peripheral origin.
Pain 1998 May
PMID:Attenuation of formalin-induced nociceptive behaviors following local peripheral injection of gabapentin. 969 74

Substance P receptor (SPR), which plays a key role in pain transmission, is known to undergo rapid agonist-dependent desensitization and internalization. The present study shows that human SPR undergoes agonist-dependent phosphorylation in intact cells. Immunoprecipitation of SPR from 32Pi-labeled Chinese hamster ovary cells stably expressing human SPR (CHO-hSPR) indicates that substance P (SP) causes a rapid (T1/2 < 1 min), dose-dependent (EC50 = 2 nM), and pronounced (5-fold over basal) phosphorylation of SPR. Because SPR in CHO-hSPR couples to Galphaq, Galphas, and Galphao (), we examined the involvement of various second messenger-activated protein kinases in SPR phosphorylation. Although increases in intracellular cyclic AMP or treatment with the calcium ionophore A23187 do not cause SPR phosphorylation, treatment with the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) causes a 2.5-fold increase in SPR phosphorylation with a T1/2 of <1 min. However, PKC inhibitor GF109203X has no effect on SP-dependent SPR phosphorylation. Furthermore, although SP treatment phosphorylates SPR on both serine and threonine residues equally, PMA treatment phosphorylates the receptor predominantly on serine residues. Two-dimensional phosphopeptide mapping data indicate that SP-dependent and PMA-dependent phosphorylations of SPR have some unique differences. Taken together, these data suggest that although activation of PKC by PMA can lead to SPR phosphorylation, PKC does not mediate SP-dependent phosphorylation of SPR. In conclusion, the present study represents the first demonstration and characterization of agonist-dependent and PMA-mediated phosphorylation of SPR in intact cells.
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PMID:Characterization of differences between rapid agonist-dependent phosphorylation and phorbol ester-mediated phosphorylation of human substance P receptor in intact cells. 1022 May 64

There is now mounting evidence supporting the hypothesis that pathological perceptual disorders described as secondary hyperalgesia and allodynia may be due to sensitization of spinal cord dorsal horn neurons. Protein kinase C (PKC) is thought to be one of the factors in the cascade of events leading from peripheral tissue damage to the sensitization of central neurons. In our experiments, we have used local microdialysis administration of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to activate PKC in the spinal cord dorsal horn in awake rats. In behavioral tests the responsiveness of the animals to von Frey filaments (1-1200 mN) and to heat stimuli applied to the hindpaws was tested. Thirty minutes after the TPA infusion the threshold for the paw withdrawal response was significantly decreased (from 160 to 6 mN) and the responses to suprathreshold stimuli were more robust. An increased mechanical sensitivity was no longer present when tested 1.5 and 5 h after the TPA application was terminated. When heat stimuli were tested, the TPA infusion resulted in a significantly prolonged time during which the animals held their hindpaws above the supporting surface after the heat stimulus (0.5 and 1.5 h after TPA), and in a decreased threshold for the heat stimulus (latency of withdrawal) 5 h after TPA. HPLC analysis of the perfusate obtained by microdialysis in vivo showed a significant increase in the extracellular levels of aspartate, glutamate, glycine and taurine, and a decrease of the glutamine level during TPA infusion. The levels of asparagine, serine, threonine and alanine did not change. Application of the inactive phorbol ester (alpha-TPA) did not evoke any change from the control values either in the AA concentrations or in the behavioral tests. Our results suggest that activation of PKC in the spinal cord evokes mechanical allodynia and thermal hyperalgesia and provides further evidence that PKC is involved in the process of the modulation of nociceptive information at the spinal cord level.
Pain 1999 Apr
PMID:The effect of phorbol esters on spinal cord amino acid concentrations and responsiveness of rats to mechanical and thermal stimuli. 1034 21


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