Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The mu-opioid receptor (MOR1) mediates the main analgesic effects of morphine and several other opioids. However, the clinical benefit of these drugs is limited by the development of tolerance and dependence. In vitro the mu-opioid receptor undergoes a rapid homologous desensitization during prolonged agonist exposure. We have recently identified the serine residues, Ser(261) and Ser(266), within the third intracellular loop as two consensus calcium/calmodulin-dependent protein kinase II (CaMKII) sites required for agonist-induced phosphorylation and desensitization of the mu-opioid receptor in HEK 293 cells. Since the specific pattern of mu-opioid receptor regulation in vivo is thought to depend on the cell- and tissue-specific complement of protein kinases, we examined the spatial relation between MOR1 and CaMKII in rat brain using specific antibodies. We found that MOR1 and CaMKII alpha which is a major CaMKII isoform expressed in the central nervous system co-exist in distinct pain-processing brain regions including the superficial layers of the spinal cord dorsal horn and dorsal root ganglia. At high power magnification it was evident that virtually all MOR1-expressing nociceptive spinal cord neurons also co-contain CaMKII. In naive or saline-treated animals the mu-opioid receptor was almost exclusively confined to the plasma membrane, while CaMKII was localized to vesicle-like structures throughout the cytoplasm. After subcutaneous administration of the mu-opioid receptor agonist, etorphine, a large proportion of the mu-opioid receptor proteins redistributed from the plasma membrane into the cytosol where it was frequently co-localized with CaMKII. Together, we identify CaMKII as a potential protein kinase, which by virtue of its colocalization with MOR1 may be in a position to phosphorylate the mu-opioid receptor and may thus contribute to the development of tolerance to opioid analgesics.
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PMID:Colocalization of the mu-opioid receptor and calcium/calmodulin-dependent kinase II in distinct pain-processing brain regions. 1114 27

The platypus (Ornithorhynchus anatinus), a uniquely Australian species, is one of the few living venomous mammals. Although envenomation of humans by many vertebrate and invertebrate species results in pain, this is often not the principal symptom of envenomation. However, platypus envenomation results in an immediate excruciating pain that develops into a very long-lasting hyperalgesia. We have previously shown that the venom contains a C-type natriuretic peptide that causes mast cell degranulation, and this probably contributes to the development of the painful response. Now we demonstrate that platypus venom has a potent action on putative nociceptors. Application of the venom to small to medium diameter dorsal root ganglion cells for 10 s resulted in an inward current lasting several minutes when the venom was diluted in buffer at pH 6.1 but not at pH 7.4. The venom itself has a pH of 6.3. The venom activated a current with a linear current-voltage relationship between -100 and -25 mV and with a reversal potential of -11 mV. Ion substitution experiments indicate that the current is a nonspecific cationic current. The response to the venom was blocked by the membrane-permeant Ca(2+)-ATPase inhibitor, thapsigargin, and by the tyrosine- and serine-kinase inhibitor, k252a. Thus the response appears to be dependent on calcium release from intracellular stores. The identity of the venom component(s) that is responsible for the responses we have described is yet to be determined but is probably not the C-type natriuretic peptide or the defensin-like peptides that are present in the venom.
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PMID:Venom from the platypus, Ornithorhynchus anatinus, induces a calcium-dependent current in cultured dorsal root ganglion cells. 1124 5

The neurological basis for painful temporomandibular disorders (TMD) and the higher prevalence of TMD pain in women than men is not known. To better define the circuitry and neurochemical mechanisms in the lower brainstem associated with noxious sensory inputs from the temporomandibular joint (TMJ) region a microdialysis method was used to measure the release of amino acid transmitters from the ventral trigeminal subnucleus interpolaris/caudalis transition region (Vi/Vc-vl). The irritant chemical, mustard oil, was injected into the TMJ region (TMJ-MO) under barbiturate anesthesia in males and normal cycling female rats. Males displayed significant increases in glutamate, serine, and glycine within 15 min after TMJ-MO and increases in citrulline occurred after a delay of 15-30 min. TMJ-MO did not enhance amino acid release in diestrus or proestrus females. GABA release was not affected by TMJ-MO in males or females. Pretreatment with morphine (3 mg/kg, i.v.) prevented the increase in amino acid release seen after TMJ-MO in males. Amino acid release at the Vi/Vc-vl transition region evoked by TMJ-MO also was prevented by prior microinjection of the GABA(A) receptor agonist, muscimol, into the most caudal portion of Vc suggesting this region acted as a critical relay for nociceptive inputs from the TMJ region. These results suggest that glutamatergic mechanisms acting at the Vi/Vc-vl transition region contribute to processing of nociceptive signals that arise from the TMJ region. These results also are consistent with the hypothesis that central neural mechanisms that integrate nociceptive inputs from deep craniofacial tissues are different in males and females.
Pain 2002 Jul
PMID:Sex differences in amino acid release from rostral trigeminal subnucleus caudalis after acute injury to the TMJ region. 1209 20

We report on serine protease activity in cercarial secretions (CSs) from the bird parasite Trichobilharzia ocellata. Using a colorigenic substrate, the biochemical properties of this enzyme were studied and its activity was compared to the homologous one in CSs from the human parasite Schistosoma mansoni. The specific serine protease activity was always 2- to 3-fold higher in CSs from T. ocellatacompared to S. mansoni. The enzyme has its optimal activity at pH 10.5, is Ca2+-dependent (inhibition with EDTA) and has a trypsin-like (inhibition with anti-pain) serine proteinase activity (inhibition with PMSF and aprotinin). The K(m) value of the serine protease from T. ocellatawas higher than that of S. mansoni, and the K(i) values for several inhibitors were generally lower for the enzyme of T. ocellatathan that of S. mansoni except for EDTA. The enzyme activities from both parasites had a molecular weight of 30 kDa in gelatin-SDS-polyacrylamide gels. The intensity of the gelatin digestion bands was stronger with the T. ocellata than with the S. mansoni enzyme.
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PMID:Biochemical comparison of the serine protease (elastase) activities in cercarial secretions from Trichobilharzia ocellata and Schistosoma mansoni. 1210 70

There is extensive evidence that spinal excitatory amino acids (EAAs) like glutamate (Glu) and aspartate (Asp) are important in the processing of nociceptive behaviors caused by incisions. To better understand EAA-induced dorsal horn sensitization caused by surgery, we examined the time course and extent of spinal amino acid (AA) release during and after a plantar incision utilizing in vivo microdialysis. We also examined the role of primary afferent input and axonal conduction by measuring spinal EAAs in rats after hindpaw denervation and in rats treated with spinal tetrodotoxin (TTX). In halothane-anesthetized rats, a microdialysis filament (200 microm diameter, 45,000 MW cut off, Hospal AN69) was passed transversely through the deep dorsal horn of the spinal cord (L4-L6). After 18-24h, the dialysis filament was perfused with artificial cerebrospinal fluid (ACSF), dialysate samples collected and analyzed for AAs (Glu, Asp, asparagine, glutamine, serine, and glycine). Rats underwent anesthetic induction with halothane followed by a plantar incision (n=8) or sham operation (n=8). AAs were also measured in incised rats that underwent hindpaw denervation (n=4), in rats that had the filament placed outside the L4-L6 spinal segments (n=7), in rats with a microdialysis catheter placed in the ventral horn at L4-L6 (n=7) and in rats treated with spinally administered TTX (n=5). AAs were measured during recovery from anesthesia and for the next 8h. In the sham-operated group, Asp and Glu did not change throughout the experiment. In rats undergoing plantar incision, Asp and Glu increased from 10 to 30 min after incision to 200+/-30 and 138+/-12 percentage of control, respectively. The EAAs returned to baseline by 1h after incision. For the other AAs, only serine and asparagine increased after incision. No increase in AA release by incision was observed after hindpaw denervation, TTX treatment or placement of the filament outside the L4-L6 segments. In rats with a filament implanted in the ventral horn (L4-L6), EAAs increased during halothane induction and sham preparation. Thus, the EAA release required an intact afferent nerve barrage and segmental excitatory nerve transmission. The incision-induced nociceptive afferent barrage increased the release of Glu and Asp in the lumbar dorsal horn for 45 min. The concentrations of AAs returned to baseline by 1h. The percentage increase is in some cases less and for a shorter period of time compared to other models of persistent pain, perhaps because the incision injury is less severe compared to others models. This profile of EAA release further explains why models of inflammation and chemical irritation do not translate well to human postoperative pain.
Pain 2002 Nov
PMID:Excitatory amino acid release in the spinal cord caused by plantar incision in the rat. 1243 60

Intrathecal pertussis toxin injection has been used as a neuropathic pain model. In the present study, its effects on cerebrospinal fluid biochemistry and nociceptive behavioral expression were examined in rats. Cerebrospinal fluid dialysate samples were collected and pertussis toxin was injected using an intrathecally implanted dialysis loop catheter; samples were collected and hyperalgesia behavior was noted every 2 days for 8 days after pertussis toxin injection. Pertussis toxin injection induced thermal hyperalgesia which peaked between day 2 and 4; no cold allodynia was observed. Pertussis toxin at all doses tested (0.5, 1, or 2 microg) also induced a significant increase in cerebrospinal fluid concentrations of aspartate and glutamate between days 2 and 8, while level of the inhibitory amino acid glycine were significantly decreased by the two higher doses of pertussis toxin. Intrathecal administration of the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosponovaleric acid (10 microg) or glycine (200 microg), inhibited pertussis toxin-induced thermal hyperalgesia. Pertussis toxin injection had no effect on serine, glutamine, and taurine concentrations. These results show that intrathecal pertussis toxin injection induces thermal hyperalgesia and it is associated with an increasing of excitatory and a decreasing of inhibitory amino acids release in the spinal cord.
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PMID:Intrathecal pertussis toxin induces thermal hyperalgesia: involvement of excitatory and inhibitory amino acids. 1257 26

Capsaicin, the main ingredient in 'hot' chili peppers, elicits burning pain by activating nociceptors. The cloned capsaicin receptor (TRPV1) is a nonselective cation channel with six transmembrane domains, and is activated not only by capsaicin but also by noxious heat (> 43 degrees C) or protons (acidification), both of which cause pain in vivo. Furthermore, analyses of mice lacking VR1 showed that VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia. Tissue damage produces an array of chemical mediators that activate or sensitize nociceptor terminals to elicit pain. Important components of this pro-algesic response are ATP and bradykinin. In cells expressing TRPV1, ATP or bradykinin increased the currents evoked by capsaicin or protons through activation of metabotropic P2Y or B2 bradykinin receptors. In the presence of ATP or bradykinin, the temperature threshold for VR1 activation was reduced from 42 degrees C to 30-35 degrees C, such that normally non-painful normal body temperatures were capable of activating TRPV1, thereby leading to the sensation of pain. Direct phosphorylation of TRPV1 by PKC epsilon was confirmed and the involved two serine residues were determined. This represents a novel mechanism through which ATP or bradykinin in response to tissue trauma might trigger the sensation of pain.
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PMID:[Molecular mechanisms of nociception]. 1288 55

The role of NMDA receptor expression and post-translational modification in the pathological and behavioral consequences of injury were examined in rats receiving spinal injections of quisqualate. Spinal cords were removed 3 days following the development of excessive grooming behavior or, if the spontaneous pain-like behavior was not observed, 13 days following injections. Western blots from the spinal tissue demonstrated that non-grooming animals had elevated protein levels of the NR1 subunit of the NMDA receptor. These subunits did not demonstrate an enhanced level of phosphorylation. NR1 protein in grooming rats was not elevated, but there was a significant increase in NR1 serine phosphorylation. These findings suggest that excitotoxic lesions of the spinal cord induce both NR1 expression and NR1 serine phosphorylation. However, the injury-induced excessive grooming behavior is only associated with phosphorylation of the NR1 subunit.
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PMID:N-methyl-D-aspartate receptor subunit expression and phosphorylation following excitotoxic spinal cord injury in rats. 1294 81

Strychnine-sensitive glycine receptors (GlyRs) inhibit neurotransmission in the spinal cord and brainstem. To better define the function of this receptor in vivo, we constructed a point mutation that impairs receptor function in the alpha1-subunit and compared these knock-in mice to oscillator (spdot) mice lacking functional GlyR alpha1-subunits. Mutation of the serine residue at amino acid 267 to glutamine (alpha1S267Q) results in a GlyR with normal glycine potency but decreased maximal currents, as shown by electrophysiological recordings using Xenopus oocytes. In addition, single-channel recordings using human embryonic kidney 293 cells indicated profoundly altered properties of the mutated GlyR. We produced knock-in mice bearing the GlyR alpha1 S267Q mutation to assess the in vivo consequences of selectively decreasing GlyR efficacy. Chloride uptake into brain synaptoneurosomes from knock-in mice revealed decreased responses to maximally effective glycine concentrations, although wild-type levels of GlyR expression were observed using 3H-strychnine binding and immunoblotting. A profound increase in the acoustic startle response was observed in knock-in mice as well as a "limb clenching" phenotype. In contrast, no changes in coordination or pain perception were observed using the rotarod or hot-plate tests, and there was no change in GABA(A)-receptor-mediated chloride uptake. Homozygous S267Q knock-in mice, like homozygous spdot mice, exhibited seizures and died within 3 weeks of birth. In heterozygous spdot mice, both decreased 3H-strychnine binding and chloride flux were observed; however, neither enhanced acoustic startle responses nor limb clenching were seen. These data demonstrate that a dominant-negative point mutation in GlyR disrupting normal function can produce a more dramatic phenotype than the corresponding recessive null mutation, and provides a new animal model to evaluate GlyR function in vivo.
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PMID:Glycine receptor knock-in mice and hyperekplexia-like phenotypes: comparisons with the null mutant. 1295 67

The functions of crucial proteins in the nervous system are modulated by kinases and phosphatases which catalyze opposing reactions of phosphorylation and dephosphorylation. During spinal cord central sensitization, serine/threonine protein phosphatase 2A (PP2A) may play an important role in determining the excitability of nociceptive neurons in the spinal cord by modulating the phosphorylation state of some critical proteins. The effects of a general inhibitor of PP2A, okadaic acid (OA), and a specific inhibitor, fostriecin, on the behavioral responses of rats following capsaicin injection were investigated in this study. Hyperalgesia was initiated by injection of capsaicin into the plantar surface of the hindpaw of rats. An intrathecal catheter was previously implanted into the subarachnoid space of the spinal cord for the administration of a variety of drugs. Rats were tested for responses to mechanical stimuli using von Frey filaments of different bending forces applied at a site outside the area of injection. Responses to heat stimuli were detected from a site near the injection area. The responses were recorded before and after injection of capsaicin with the perfusion of ACSF, OA negative control, OA or fostriecin at different time points. The results demonstrated that secondary mechanical hyperalgesia and allodynia can be induced by the intradermal injection of capsaicin. Compared to administration of ACSF or the OA negative control, infusion of the phosphatase inhibitor OA or of fostriecin into the subarachnoid space enhanced the secondary mechanical hyperalgesia and allodynia by making the intradermal capsaicin-induced hyperalgesia and allodynia last longer.
Pain 2003 Dec
PMID:The effects of protein phosphatase inhibitors on nociceptive behavioral responses of rats following intradermal injection of capsaicin. 1465 28


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