Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the sites phosphorylated on acetyl-CoA carboxylase by three protein kinases which have been shown to inactivate the enzyme, i.e. cyclic-AMP-dependent protein kinase, acetyl-CoA carboxylase kinase-2 (ACK2, purified from rat mammary gland) and the AMP-activated protein kinase (formerly called acetyl-CoA carboxylase kinase-3, purified from rat liver). Each protein kinase phosphorylates two out of three sites (termed 1-3) which have been established by amino acid sequencing. The two sites phosphorylated by each kinase can be recovered on separate peptides, TC1 and TC2, derived by combined digestion of the native enzyme by trypsin and chymotrypsin: TC1 = Ser-2Ser(P)-Met-3Ser(P)-Gly-Leu; TC2 = Arg-Met-1Ser(P)-Phe- Cyclic-AMP-dependent protein kinase phosphorylates sites 1 and 2 exclusively, whereas the AMP-activated protein kinase phosphorylates sites 1 and 3, plus at least one other minor site. ACK2 phosphorylates site 1 and, more slowly, an unidentified site(s) within TC1. We have also established the structures of the single major phosphopeptides (T1 and C1 respectively) which are recovered by HPLC after acetyl-CoA carboxylase phosphorylated by cyclic-AMP-dependent protein kinase is digested with trypsin or chymotrypsin alone. T1 is related to TC1, and has the structure: Ser-Ser(P)-Met-Ser-Gly-Leu-His-Leu-Val-Lys. C1 is identical with TC2. We have carried out studies on the correlation of the activity of acetyl-CoA carboxylase with the occupancy of sites 1, 2 and 3 during phosphorylation by each of the three protein kinases. The results suggest that phosphorylation of site 3 is primarily responsible for the large decrease in Vmax produced by the AMP-activated protein kinase, while phosphorylation of site 1 may be primarily responsible for the increase in A0.5 for citrate and more modest depression of Vmax produced by cyclic-AMP-dependent protein kinase and ACK2. Our results emphasize that amino acid sequence information is essential in the unequivocal interpretation of data from phosphopeptide mapping experiments and allow a more complete interpretation of previous data on phosphorylation of acetyl-CoA carboxylase in intact cells. They also open the way to experiments which could establish the physiological roles of these protein kinases in the control of fatty acid synthesis.
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PMID:Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. 290 Jan 38

Systemic injection of naloxone (NAL), an opioid-receptor antagonist, significantly elevates systolic blood pressure (SBP) in anesthetized hypovolemic monkeys, providing indirect evidence that endogenous opioids contribute to cardiovascular depression during shock. The purpose of this study was to identify specific centrally located opioid receptor sites that participate in SBP regulation under normovolemic and hypovolemic conditions. In 6 monkeys, bilateral guide cannulae were stereotaxically implanted above areas ranging from the diencephalon to the lower medulla. Microinjections (1 microliter) of D- Ala2-Met-enkephalinamide (DAME) (3.4-27.2 nM) into normovolemic unanesthetized monkeys reduced SBP by 10-65 mm Hg in a dose-related fashion. Subsequent injection of NAL (12.2 nM) attenuated this hypotensive response. Heart rate fell 20-40 bpm with DAME, but not in response to dose. In the anesthetized animal rendered hypotensive (SBP = 45 mm Hg) by hemorrhage. NAL injected into predetermined DAME-sensitive sites failed to increase SBP more than 5 mm Hg. Even consecutive injections into multiple sites elevated SBP only 20 mm Hg. We conclude that the centrally located opioid-sensitive sites tested exert only a mild influence in mediating hemorrhagic hypotension.
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PMID:Effects of opiate receptor drugs injected intracerebrally into the normovolemic and hypovolemic monkey. 301 Feb 58

Intracellular recordings were made from neurons of the rat locus coeruleus contained within a brain slice maintained in vitro. When applied to the slice in known concentrations the selective kappa opioid receptor agonist trans-(+)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide methane sulphonate (U50488) (0.01-1 microM) produced a concentration-dependent depression of the excitatory post-synaptic potential evoked by electrical stimulation of afferent inputs to the locus coeruleus. This effect was antagonized by naloxone with an apparent dissociation equilibrium constant (Kd) of 28 nM. U50488 did not completely abolish the EPSP. Over the same concentration range U50488 had no effect on the resting membrane potential, input resistance or action potential waveform of locus coeruleus neurons, nor did U50488 depress the depolarization produced by local application of L-glutamic acid. The mu opioid receptor agonists [D-Ala2, NMe Phe4, Gly-ol5] enkephalin (0.003-1 microM) and [D-Ala2, NMe Phe4, Met(O)5] enkephalinol (0.003-1 microM) caused a membrane hyperpolarization concomitant with a fall in neuronal input resistance. These effects were concentration-dependent and antagonized by naloxone with an apparent Kd of 1.5 nM. Mu agonists also caused a depression of the tetrodotoxin resistant action potential. An in vitro autoradiographic study of [3H]bremazocine binding within the locus coeruleus revealed that, although the majority of binding appears to be to mu sites, a significant proportion was displaceable by unlabelled U50488 and thus represented kappa binding sites. The possibility that kappa opioid receptors may be located pre-synaptically within the locus coeruleus, and that activation of these receptors depresses excitatory synaptic input, is discussed.
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PMID:Kappa opioid receptor activation depresses excitatory synaptic input to rat locus coeruleus neurons in vitro. 303 41

Synaptic transmission between mechanosensory and motor neurons of the gill withdrawal reflex in Aplysia can undergo both short-term and long-term modulation. One form of short-term synaptic depression lasting minutes can be evoked by the peptide Phe-Met-Arg-Phe-amide (FMRFamide), and is mediated by the lipoxygenase pathway of arachidonic acid. We report here using cell culture, that the same monosynaptic sensory-to-motor component of the gill withdrawal reflex can also undergo long-term synaptic depression lasting 24 h after five applications of FMRFamide over a 2-h period. The long-term depression evoked by FMRFamide is transmitter-specific. Dopamine or low-frequency stimulation of sensory neurons, which also produce short-lasting synaptic depression in vivo, failed to evoke a long-term change. As is the case for long-term presynaptic facilitation of this connection with serotonin, the long-term depression, but not the short-term, can be blocked when applications of FMRFamide are given in the presence of anisomycin, a reversible inhibitor of protein synthesis. Thus, heterosynaptic depression parallels heterosynaptic facilitation in having a long-term as well as a short-term form, and in both cases the long-term modulation requires the synthesis of gene products not essential for the short-term changes.
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PMID:Long-term heterosynaptic inhibition in Aplysia. 336 86

The purpose of the present study was to make a functional dissection of the respiratory action of opioids, by their restricted application to the ventral surface of the medulla oblongata and to the rostro-dorsal surface of the pons in cats. The effects were compared to those induced after intracerebroventricular (i.c.v.) injection. Two mu-agonists, morphine and D-Ala2-Me-Phe4-Met(O)ol5-enkephalin (FK-33824), and the delta-agonist D-Ala2-D-Leu5-enkephalin (DADLE) were used. When applied to the ventral medullary surface, the opioids selectively depressed the generating mechanisms for tidal volume and the response to CO2, whereas the frequency was increased. The application to the rostral dorsal surface of the pons was followed by a selective depression of the respiratory frequency. By intracerebroventricular administration, the opioids depressed both the tidal volume and frequency generating mechanisms. The effects were always reversed by naloxone. The pontine structures were more sensitive to the action of the opioids than were the medullary centres. These findings suggest that the opioids can interact with different populations of respiratory neurones and that the respiratory output differs depending on the group of neurones selectively affected and the function they subserve in regulating respiratory activity.
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PMID:Differential respiratory patterns induced by opioids applied to the ventral medullary and dorsal pontine surfaces of cats. 392 84

Certain developmental abnormalities have been associated with environmental exposure to lead and our previous studies have indicated that the endogenous opioid system is disrupted by this metal. In connection with this we report the ontogeny of proenkephalin products in the rat striatum determined by combined HPLC and bioassay and the effects of low-level lead exposure on this ontogeny. The development of Met-enkephalin levels was dissimilar from that of the other proenkephalin products, Met-enkephalyl-Arg6-Phe7, Met-enkephalyl-Arg6-Gly7-Leu8 and Leu-enkephalin. The ratios of Met-enkephalin containing peptides to Leu-enkephalin was less than the 6:1 ratio predicted from the proenkephalin structure. Lead (administered in the maternal drinking water, from conception to weaning at 100, 300 and 1000 ppm) caused a dose-related depression of the levels of proenkephalin products in rat striatum at 10, 21 and 30 days after birth. The most pronounced effects were observed at 10 days and the most persistent effects were seen with Met-enkephalin. Peak blood lead levels were below 45 micrograms/100 ml in the 100 and 300 ppm lead-dosed groups and in all lead-dosed groups at 10 days after birth. It is suggested that lead may have inhibitory effects on proenkephalin-processing enzymes.
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PMID:Ontogenesis of proenkephalin products in rat striatum and the inhibitory effects of low-level lead exposure. 404 20

ACTH1-24 (0.5 or 10 micrograms = 0.17 or 3.45 nmol) and D-Ala2-Met-enkephalinamide (DAME; 10 micrograms = 17.05 nmol) were injected unilaterally into the hippocampus of freely moving rats to examine their effects on EEG activity, DC potentials and behavior. In 85% of the rats DAME elicited spreading depression (SD) with epileptiform discharges preceding and following the wave of SD. The following behavioral changes were recorded. DAME- and KCl-induced SD were accompanied by an increase in locomotor activity and wet-dog shaking behavior, which occurred only during the period of SD. After a wave of SD induced by DAME a biphasic pattern of activity, consisting of an initial depression in locomotion followed by hyperactivity, appeared in 59% of the rats. ACTH1-24 elicited SD in 13% of the rats tested. Neither the dosage of ACTH1-24 nor the strain of rats influenced the occurrence of SD and the incidence of ACTH-induced grooming behavior. SD induced by KCl also resulted in excessive grooming comparable to that induced by ACTH1-24. In the case of KCl-induced SD, grooming began directly after the injection of KCl and was frequently interrupted by short periods of locomotion. ACTH-induced grooming had a later onset and episodes of stretching and yawning were observed. It can be concluded that the behavioral effects of the injection of DAME are unspecific responses to SD and seizure activity. However, ACTH-induced grooming is not solely a byproduct of SD, since it occurred also in the absence of SD.
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PMID:Electroencephalographic spreading depression and concomitant behavioral changes induced by intrahippocampal injections of ACTH1-24 and D-Ala2-Met-enkephalinamide in the rat. 608 54

Motilin, [Met]enkephalin, [Leu]enkephalin, somatostatin, taurine, gamma-aminobutyric acid (GABA), and glycine were tested for their effects on Deiters neurons of the lateral vestibular nucleus in rabbits. Iontophoresis was carried out with multibarrelled micropipettes. All four peptides and three amino acids produced depression of neuron firing. No facilitatory responses were observed. The depressant action of each peptide when iontophoresed alone was dose-dependent and was rapid in onset and recovery. Their characteristic actions suggest the possibility of their independent roles as strong inhibitors, although the experimental paradigm does not allow conclusions about the individual potency of each peptide. When GABA was administered together with motilin, [Met]enkephalin, or somatostatin, the effects of the peptide and GABA were additive, producing depression greater than that with application of either substance alone. When GABA was applied in conjunction with [Leu]enkephalin, more complex interactions were observed. At low iontophoretic currents, [Leu]enkephalin antagonized the action of GABA, producing a depression less than that of GABA alone and of considerably slower onset, suggesting an additional modulatory effect. These observations support the conclusion that all substances tested are chemical mediators in the lateral vestibular nucleus and [Leu]enkephalin may be a neuromodulator as well. Because recent immunocytochemical studies indicate that Purkinje cells in the cerebellar cortex are chemically heterogeneous and exhibit immunoreactivity for motilin, taurine, the enkephalins, and somatostatin, as well as for the GABA-synthesizing enzyme glutamic acid decarboxylase, it is suggested that the Purkinje cell projections to vestibular and cerebellar nuclei are multimodal in their chemical coding. The uniformly depressant action of the peptides and amino acids reported here is consistent with earlier observations that Purkinje cells exert an inhibitory influence on the vestibular and central cerebellar nuclei.
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PMID:Inhibitory effects of motilin, somatostatin, [Leu]enkephalin, [Met]enkephalin, and taurine on neurons of the lateral vestibular nucleus: interactions with gamma-aminobutyric acid. 612 70

In order to determine the importance of opioid peptides in the central control of wakefulness, the synthetic analogue of Met-Enkephalin, FK 33-824 (d-Ala-2-Phe-Met-(O)-ol-Enkephalin) which is more resistant to enzymatic degradation, was perfused in increasing concentrations (20, 100, 200, and 400 micgrograms/ml) through the fourth cerebral ventricle of the conscious dog. In the EEG (Power-spectral density in continuous acquisition) high concentrations (200--400 micgrograms/ml) induce slowing (theta--delta) with overlying beta-activity. This was reflected in the animals behaviour resulting in a sleep-like state which in spite of the administration of high doses of the antagonist Naloxone (100 micrograms/kg i.v.) sustained for 12 hours. A simultaneously dose-related respiratory depression (drop in arterial pO2 and an increase in arterial pCO2) was reversed by Naloxone. It is concluded that the opioid peptide FK 33-824 induces EEG-slowing which is mediated by a subpopulation of opiate-binding sites, possibly the kappa-receptors. These receptors are different from binding sites mediating respiratory depression (micro-receptors) as they interact with the opiate-antagonist Naloxone.
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PMID:[Naloxone-resistant EEG slowing induced by the synthetic opioid peptide FK 33-824 in the 4th cerebral ventricle of the dog]. 629 96

The respiratory depression induced by two mu-opiate agonists morphine and Tyr-D-Ala-Gly-N-Me-Phe-Met(O)-ol (FK-33824), and two delta-agonists Tyr-D-Ala-Gly-Phe-D-Leu (DADLE) and Tyr-D-Ser-Gly-Phe-Leu-Thr (D-Ser2-Thr6) was studied in rats by using the intracerebroventricular route. The four opioids caused a dose-dependent depression of respiratory frequency down to apnea but high doses of morphine elicited motor activation and seizure activity. FK-33824 was the most potent, followed by DADLE, D-Ser2-Thr6 and morphine. The in vivo apparent pA2 values were determined for naloxone against FK-33824, DADLE and D-Ser2-Thr6. The pA2 value of naloxone interacting with the mu-agonist FK-33824 was significantly lower than those obtained against the two delta-agonists. It is proposed that different types of opiate receptors are involved in the opiate-induced respiratory depression.
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PMID:Interaction of naloxone with mu- and delta-opioid agonists on the respiration of rats. 630 57


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