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91.
Galanin is a 29- to 30-aa-long neuropeptide affecting feeding, cognitive, and sexual behavior. It exerts its effects through galanin receptors 1, 2 and 3, which are all seven transmembrane domain G-protein coupled receptors (GPCRs). The GPCRs have been shown to function as monomers, homodimers, heterodimers and oligomers. In this study, we examined the extent of galanin receptor 1 (GalR1) dimerization and internalization in living CHO cells using fluorescence resonance energy transfer (FRET) and time lapse confocal imaging. Ratio imaging analysis and emission spectral analysis revealed substantial homodimerization of GalR1. In addition, internalization of GalR1 after 1h of agonist stimulation with the GalR1 agonist galanin (1-29) was observed with time lapse fluorescence imaging, whereas stimulation with the GalR2 specific agonist galanin (2-11) did not lead to internalization. Treatment of GalR1 transfected cells with the non-selective adenylyl cyclase activator forskolin influenced the rate of internalization when administered together with galanin (1-29). These results indicate that GalR1 can act as a dimer on the cell surface and that receptor desensitization and internalization was observed after stimulation with the agonist galanin (1-29). Western blots further confirm the FRET data that GalR1-XFP dimerizes and can be detected in the cell as a monomer or dimer using antibodies to XFP. Internalization and dimerization of GalR1 is shown, contributing to the regulation of galanergic signaling. 相似文献
92.
Florén A Sollenberg U Lundström L Zorko M Stojan J Budihna M Wheatley M Martin NP Kilk K Mazarati A Bartfai T Lindgren M Langel U 《Neuropeptides》2005,39(6):714-558
Galnon was first reported as a low molecular weight non-peptide agonist at galanin receptors [Saar et al. (2002) Proc. Natl. Acad. Sci. USA 99, 7136-7141]. Following its systemic administration, this synthetic ligand affected a range of important physiological processes including appetite, seizures and pain. Physiological activity of galnon could not be explained solely by the activation of the three known galanin receptors, GalR1, GalR2 and GalR3. Consequently, it was possible that galnon generates its manifold effects by interacting with other signaling pathway components, in addition to via GalR1-3. In this report, we establish that galnon: (i) can penetrate across the plasma membrane of cells, (ii) can activate intracellular G-proteins directly independent of receptor activation thereby triggering downstream signaling, (iii) demonstrates selectivity for different G-proteins, and (iiii) is a ligand to other G-protein coupled receptors (GPCRs) in addition to via GalR1-3. We conclude that galnon has multiple sites of interaction within the GPCR signaling cascade which mediate its physiological effects. 相似文献
93.
Leranth C Prange-Kiel J Frick KM Horvath TL 《Cerebral cortex (New York, N.Y. : 1991)》2004,14(5):503-510
The hippocampus plays a major role in learning and memory and its morphology and function are readily affected by gonadal hormones in female non-human primates. We sought to determine whether the gonads also affect pyramidal cell spine synapse density in the CA1 hippocampal area of male primates. Unbiased electron microscopic stereological calculations were performed to determine the volumetric density of pyramidal cell spine synapses and semiquantitative analyses on the surface density of glial fibrillary acidic protein-containing glia processes and the diameter of pyramidal cell apical dendrites in the CA1 area of intact and orchidectomized (1 month) St Kitts vervet monkeys (Chlorocebus aethiops sabaeus). The volumetric density (number of spine synapse/ micro m(3)) of spine synapses was significantly lower (40%) in the gonadectomized animals than in control monkeys; conversely, the density of glia processes was significantly higher (15%) and the diameter of dendritic shafts located in this area was also larger (30%) in the orchidectomized animals than in the controls. Strikingly, when compared to female values, intact male primates had lower spine synapse densities than either intact or ovariectomized females. Since the primate hippocampus is very similar to that of a human's, the present observations suggest that physiological levels of circulating androgen hormones are necessary to support normal spine synapse density in the CA1 stratum radiatum of human male hippocampus. 相似文献
94.
95.
Kilk K Elmquist A Saar K Pooga M Land T Bartfai T Soomets U Langel U 《Neuropeptides》2004,38(5):316-324
In this work, we have targeted positions 18-38 of the human galanin receptor type 1 (GalR1) mRNA coding sequence with different peptide nucleic acid (PNA) oligomers. This region has previously been shown to be a good antisense region and therefore we aimed to identify the subregions and/or thermodynamic parameters determining the antisense efficacy. Nine different PNA oligomers were conjugated to a cell-penetrating peptide, transportan, to enhance their cellular uptake. Concentration-dependent down-regulation of GalR1 protein expression in human melanoma cell line Bowes was measured by radioligand binding assay. No reduction of GalR1 mRNA level was observed upon PNA treatment, thus, the effect was concluded to be translational arrest. Judging from the EC50 values, antisense PNA oligomers targeting regions 24-38 (EC50=70 nM) or 27-38 (EC50=80 nM) were the most potent suppressors of protein expression. No parameter predicted by M-fold algorithm was found to correlate with the measured antisense activities. Presence of some subregions was found not to increase antisense efficiency of PNA. Presence of a short unpaired triplet between nucleotides 33 and 35 in the target region was, on the other hand, found to be the most critical for efficient GalR1 down-regulation. Thus, the results are of high impact in designing antisense oligomers. Specific results of this study demonstrate 20-fold more efficient antisense down-regulation of GalR1 as achieved before. 相似文献
96.
Szapary L Horvath B Marton Z Alexy T Kesmarky G Habon T Szots M Koltai K Juricskay I Czopf J Toth K 《CNS drugs》2004,18(3):165-172
97.
98.
Gestational trophoblastic diseases are interrelated conditions characterized by abnormal growth of chorionic tissues with various propensities for local invasion and metastasis. Complete mole is a unique conception in that all nuclear DNA is paternally derived and all cytoplasmic DNA is maternally derived. In contrast, partial mole generally has a triploid karyotype, where the extra haploid set of chromosomes is paternally derived: Gestational trophoblastic diseases are characterized by altered expression of several growth regulatory factors and oncogenes. While differences in expression of oncoproteins may be important to the development of gestational trophoblastic disease, the precise molecular changes that are critical to pathogenesis remain unknown. 相似文献
99.
OBJECTIVE: We tested whether lipopolysaccharide (LPS)-induced murine preterm birth was delayed by tyrphostins (inhibitors of tyrosine kinases). STUDY DESIGN: The tyrphostins, AG126 or AG1288, or the prostaglandin endoperoxide H synthase-2 (PGHS-2) inhibitor, NS-398, were administered 2 h before LPS, with LPS, or 2 h after LPS and their effect on gestational length was measured. RESULTS: Only tyrphostins and NS-398 administered 2 h before LPS successfully delayed preterm birth (p < 0.05). CONCLUSIONS: Both tyrphostins AG126 and AG1288 as well as NS-398 inhibited LPS induced preterm birth to the time of normal birth. 相似文献
100.
Ruttner Z Ivanics T Slaaf DW Reneman RS Toth A Ligeti L 《Journal of the Society for Gynecologic Investigation》2002,9(5):294-298
OBJECTIVE: It has been well established that oxytocin (OXT) increases intracellular free calcium ([Ca(2+)](i)) by targeting both intracellular and extracellular stores, but the mechanisms involved in the increase through activation with prostaglandin F(2alpha) (PGF(2alpha)) are still incompletely understood. This study was designed to elucidate the source(s) of increased [Ca(2+)](i) in response to PGF(2alpha) (10(-6) M) or OXT (10(-8) M) administration in the near-term rat myometrium. METHODS: The animals were divided into an in vitro group (n= 8), where the developed tension of uterine strips was assessed, and an in vivo group (n= 5), where a lobe of the uterus with intact innervation and circulation was loaded with the fluorescent indicator Indo-1 AM to assess [Ca(2+)](i). RESULTS: PGF(2alpha) and OXT induced a 30.1% and 35.9%, respectively, increase in developed tension in the potassium chloride-depolarized myometrial strips. Nifedipine reduced the PGF(2alpha) and OXT increased tension by 65.8% and 49.4%, respectively. In vivo, both PGF(2alpha) and OXT increased [Ca(2+)](i) in the potassium chloride-depolarized uterine muscle by 35.7% and 44.6%, respectively, increases similar to the rises in tension in vitro. Nifedipine reduced these effects of PGF(2alpha) and OXT by 45.3% and 39.6%. CONCLUSION: These findings indicate that in near-term myometrium the source of increased [Ca(2+)](i) after administration of PGF(2alpha), similar to OXT, is both extracellular and intracellular. 相似文献