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排序方式: 共有220条查询结果,搜索用时 46 毫秒
91.
Zohreh T. Farahbakhsh David W. Deamer Nancy M. Lee Horace H. Loh 《Journal of neurochemistry》1986,46(3):953-962
A new method using lysophosphatide and acyl-CoA as detergents has been used to solubilize the rat brain opiate receptor. After solubilization, lysophosphatide and acyl-CoA can be almost completely removed by an enzymatic reaction that uses an acyltransferase from rat liver microsomes and reconstitutes the solubilized receptor in membranous vesicles. Morphological studies performed with negative staining and freeze-fracture electron microscopy revealed that the general appearance and intramembrane particle distribution of fracture faces in the reconstituted membrane are similar to those of the native membrane; this indicates that hydrophobic protein components of the original membrane were incorporated during reconstitution. Reconstituted membrane, however, contained higher levels of phosphatidylcholine and lower levels of cholesterol. The activities of the membrane-bound enzymes Na+, K+-ATPase and Ca2+, Mg2+-ATPase in the reconstituted system were 24 and 3%, respectively, those of the native membrane. Although binding of opiate ligands to the reconstituted membrane was stereospecific and saturable, higher concentrations of some of the unlabeled ligands were required to inhibit binding of the radiolabeled ligands. These changes in receptor characteristics are likely due to changes in lipid composition, physical state, and/or distribution of the lipids in the reconstituted membrane bilayer. This conclusion is supported by an increase in the affinity of opiate ligands for reconstituted membrane after adjustment of the latter's lipid composition to match more closely that of the original membrane. This was accomplished by treatment with phospholipid exchange protein to remove the excess phosphatidylcholine and by incorporation of cholesterol into the reconstituted membrane. 相似文献
92.
The regulation of adult neurogenesis by opiates has been implicated in modulating different addiction cycles. At which neurogenesis stage opiates exert their action remains unresolved. We attempt to define the temporal window of morphine’s inhibition effect on adult neurogenesis by using the POMC-EGFP mouse model, in which newborn granular cells (GCs) can be visualized between days 3–28 post-mitotic. The POMC-EGFP mice were trained under the 3-chambers conditioned place preference (CPP) paradigm with either saline or morphine. We observed after 4 days of CPP training with saline, the number of EGFP-labeled newborn GCs in sub-granular zone (SGZ) hippocampus significantly increased compared to mice injected with saline in their homecage. CPP training with morphine significantly decreased the number of EGFP-labeled GCs, whereas no significant difference in the number of EGFP-labeled GCs was observed with the homecage mice injected with the same dose of morphine. Using cell-type selective markers, we observed that morphine reduced the number of late stage progenitors and immature neurons such as Doublecortin (DCX) and βIII Tubulin (TuJ1) positive cells in the SGZ but did not reduce the number of early progenitors such as Nestin, SOX2, or neurogenic differentiation-1 (NeuroD1) positive cells. Analysis of co-localization between different cell markers shows that morphine reduced the number of adult-born GCs by interfering with differentiation of early progenitors, but not by inducing apoptosis. In addition, when NeuroD1 was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. These results suggest that under the condition of CPP training paradigm, morphine affects the transition of neural progenitor/stem cells to immature neurons via a mechanism involving NeuroD1. 相似文献
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94.
95.
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98.
David A. Johnson Steven C. Merlone Horace H. Loh George L. Ellman 《Journal of neurochemistry》1978,31(3):713-717
The affinities of 5-hydroxy-[3H]tryptamine (5-HT) for cerebroside sulfate, 1-phosphatidylinositol, 1-phosphatidylinositol 4-phosphate, 1-phosphatidylinositol 4,5-bisphosphate, phosphatidic acid, and phosphatidyl serine were determined in an aqueous medium. They were observed to be, in general, much lower than and poorly correlated with the values previously reported by Johnson et al (1977a), measured in isobutanol. This suggested that these lipids probably are not 5-HT receptors and that drug affinities measured in organic media must be evaluated with caution. 相似文献
99.
100.
Lei Zhang Hui Zhao Yu Qiu Horace H. Loh Ping-Yee Law 《The Journal of biological chemistry》2009,284(4):1990-2000
Recent studies have revealed that in G protein-coupled receptor signalings
switching between G protein- and β-arrestin (βArr)-dependent
pathways occurs. In the case of opioid receptors, the signal is switched from
the initial inhibition of adenylyl cyclase (AC) to an increase in AC activity
(AC activation) during prolonged agonist treatment. The mechanism of such AC
activation has been suggested to involve the switching of G proteins activated
by the receptor, phosphorylation of signaling molecules, or receptor-dependent
recruitment of cellular proteins. Using protein kinase inhibitors, dominant
negative mutant studies and mouse embryonic fibroblast cells isolated from Src
kinase knock-out mice, we demonstrated that μ-opioid receptor
(OPRM1)-mediated AC activation requires direct association and activation of
Src kinase by lipid raft-located OPRM1. Such Src activation was independent of
βArr as indicated by the ability of OPRM1 to activate Src and AC after
prolonged agonist treatment in mouse embryonic fibroblast cells lacking both
βArr-1 and -2. Instead the switching of OPRM1 signals was dependent on
the heterotrimeric G protein, specifically Gi2 α-subunit.
Among the Src kinase substrates, OPRM1 was phosphorylated at Tyr336
within NPXXY motif by Src during AC activation. Mutation of this Tyr
residue, together with mutation of Tyr166 within the DRY motif to
Phe, resulted in the complete blunting of AC activation. Thus, the recruitment
and activation of Src kinase by OPRM1 during chronic agonist treatment, which
eventually results in the receptor tyrosine phosphorylation, is the key for
switching the opioid receptor signals from its initial AC inhibition to
subsequent AC activation.Classical G protein-coupled receptor
(GPCR)2 signaling
involves the activation of specific heterotrimeric G proteins and the
subsequent dissociation of α- and βγ-subunits. These G
protein subunits serve as the activators and/or inhibitors of several effector
systems, including adenylyl cyclases, phospholipases, and ion channels
(1). However, recent studies
have shown that GPCR signaling deviates from such a classical linear model.
For example, in kidney and colonic epithelial cells, protease-activated
receptor 1 can transduce its signals through either Gαi/o or
Gαq subunits via inhibition of small GTPase RhoA or
activation of RhoD. Thus, RhoA and RhoD act as molecular switches between the
negative and positive signaling activity of protease-activated receptor 1
(2). Another example is the
ability of β2-adrenergic receptor to switch from
Gs-dependent pathways to non-classical signaling pathways by
coupling to pertussis toxin-sensitive Gi proteins in a
cAMP-dependent protein kinase/protein kinase C phosphorylation-dependent
manner. In this case, the phosphorylation-induced switch in G protein coupling
provides the receptor access to alternative signaling pathways. For
β2-adrenergic receptors, this leads to a
Gi-dependent activation of MAP kinase
(3,
4). Furthermore the involvement
of protein scaffolds, such as β-arrestins in the MAP kinase cascade,
could also alter the GPCR signaling
(5–8).
Hence the formation of “signaling units” or
“receptosomes” would influence the GPCR signaling process and
destination.For opioid receptors, which are members of the rhodopsin GPCR subfamily
receptors, signal switching is also observed. Normally opioid receptors
inhibit AC activity, activate the MAP kinases and Kir3 K+ channels,
inhibit the voltage-dependent Ca2+ channels, and regulate other
effectors such as phospholipase C
(9). However, during prolonged
agonist treatment, not only is there a blunting of these cellular responses
but also a compensatory increase in intracellular cAMP level, which is
particularly significant upon the removal of the agonist or the addition of an
antagonist such as naloxone
(10–12).
This compensatory adenylyl cyclase activation phenomenon has been postulated
to be responsible for the development of drug tolerance and dependence
(13). The observed change from
receptor-mediated AC inhibition to receptor-mediated AC activation reflects
possible receptor signal switching. Although the exact mechanism for such
signal changes has yet to be elucidated, activation of specific protein
kinases and subsequent phosphorylation of AC isoforms
(14,
15) and other signaling
molecules (16) have been
suggested to be the key for observed AC activation. Among all the protein
kinases studied, involvement of protein kinase C, MAP kinase, and Raf-1 has
been implicated in the activation of AC
(17–19).
Alternative mechanisms, such as agonist-induced receptor internalization and
the increase in the constitutive activities of the receptor, also have been
suggested to play a role in increased AC activity after prolonged opioid
agonist treatment (20).
Earlier studies also implicated the switching of the opioid receptor from
Gi/Go to Gs coupling during chronic agonist
treatment (21). Regardless of
the mechanism, the exact molecular events that lead to the switching of opioid
receptor from an inhibitory response to a stimulatory response remain
elusive.Src kinases, which are members of the nonreceptor tyrosine kinase family,
have been implicated in GPCR function because several Src family members such
as cSrc, Fyn, and Yes have been reported to be activated by several GPCRs,
including β2-
(22) and β3
(23)-adrenergic,
M2- (24) and
M3 (25)-muscarinic,
and bradykinin receptors (26).
The GPCRs that are capable of activating Src predominantly couple to
Gi/o family G proteins
(27). Src kinases appear to
associate with, and be activated by, GPCRs themselves either through direct
interaction with intracellular receptor domains or by binding to
GPCR-associated proteins, such as G protein subunits or β-arrestins
(27). Src kinase has been
reported to be activated by κ-
(28) and δ
(29)-opioid receptors and
regulate the c-Jun kinase and MAP kinase activities. Src kinase within the
nucleus accumbens has been implicated in the rewarding effect and
hyperlocomotion induced by morphine in mice
(30). However, it is not clear
whether the Src kinase is activated and involved in the signal transduction in
AC activation after chronic opioid agonist administration.Previously we reported that the lipid raft location of the receptor and the
Gαi2 proteins are two prerequisites for the observed increase
in AC activity during prolonged agonist treatment
(31,
32). Because various protein
kinases including Src kinases and G proteins have been shown to be enriched in
lipid rafts (33), the roles of
these cellular proteins in the eventual switching of opioid receptor signals
from inhibition to stimulation of AC activity were examined in the current
studies. We were able to demonstrate that the association with and subsequent
activation of Src kinase by the μ-opioid receptor (OPRM1), which leads to
eventual tyrosine phosphorylation of OPRM1, are the cellular events required
for the switching of opioid receptor signaling upon chronic agonist
treatment. 相似文献