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At least 883 records · Page 49Linked to original sources
PubMed1996

Lack of effect of chronic antidepressant treatment on Gs and Gi alpha-subunit protein and mRNA levels in the rat cerebral cortex.

Experimental evidence indicates that chronic antidepressant treatment in rats modifies the central nervous system beta-adrenoceptor signaling pathway at multiple sites including receptor, G-protein, adenylyl cyclase, and protein kinase A. In the present study, we examined the postreceptor effect of antidepressant treatment on the protein and mRNA levels of stimulatory and inhibitory C protein alpha-subunits (G alpha s and G alpha i) and beta-subunits in rats infused continuously with various antidepressants for 21 days. Chronic treatment with tricylic (desipramine and amitriptyline) and monoamine oxidase inhibiting (tranylcypromine) antidepressants did not significantly affect the immunoreactivity levels of G alpha s (both 45- and 52-kDa species), G alpha i1, G alpha i2, G beta 36, and beta 35 in rat cerebral cortex. Similarly, the levels of mRNA encoding these G protein subunits remained unchanged subsequent to these drug treatments. In contrast, cortical beta-adrenoceptor number was significantly decreased by these treatments. These results suggest that the adaptive changes of rat cerebral cortical beta-adrenoceptor-adenylyl cyclase system often seen after chronic antidepressant treatment are not accompanied by changes in the abundance and gene expression of G alpha s, G alpha i, or G beta proteins.

Analysis of Variance↗
PubMed1991

mRNA and protein levels of the stimulatory guanine nucleotide regulatory protein Gs are lower in the testis of obese (ob/ob) mice.

Probing of total testis RNA with a cDNA corresponding to the alpha s subunit of the guanine nucleotide regulatory protein (G-protein) showed that levels of mRNA were markedly reduced in the ob/ob mouse compared to its +/+ control. The lowered level of mRNA resulted in lowered protein synthesis as shown by a marked decrease in both the 48,000 and 42,000 Mr peptides detected by (1) cholera toxin ribosylation, (2) immunodetection with an antibody specific for alpha s. This was not the result of overall lowered protein synthesis since the levels of alpha i2 and the beta subunits were unchanged. In the kidney there was no change in the levels of the alpha s subunit in obese membrane preparations. Lowered levels of alpha s were not correlated with changes in adenylyl cyclase activity. This suggests that in these membranes the G-protein subunit(s) are present in excess compared to the catalytic unit of adenylyl cyclase and that in the testis the G-proteins may be of more importance in other signalling pathways necessary for normal gonadal development and fertility.

Adenosine Diphosphate↗
PubMed1993

Adaptive changes in the number of Gs- and Gi-proteins underlie adenylyl cyclase sensitization in morphine-treated rat striatal neurons.

In the present study we investigated the possible role of changes in the number of membrane-bound G-proteins in the sensitization of dopamine D1 receptor-stimulated adenylyl cyclase, observed in primary cultures of rat striatal neurons chronically exposed to morphine. Whereas exposure of these neurons to 10 microM morphine for 7 days caused a profound increase in cyclic AMP production, induced by the dopamine D1 receptor agonist SKF 38393 (1 microM), Scatchard analysis of [125I]SCH 23982 binding to membrane preparations revealed that neither the Bmax nor the Kd values of dopamine D1 receptor binding sites were affected. Interestingly, immunoblotting experiments revealed an increase (of more than 50%) in the number of stimulatory G-proteins (G alpha s) in neurons displaying an enhanced adenylyl cyclase activity. In morphine-treated neurons, the number of inhibitory G-proteins (G alpha i) appeared to be slightly reduced (by about 16%). Moreover, the observation that cholera toxin (0.1 nM)-stimulated cyclic AMP production, unlike that induced by forskolin (1 microM), was enhanced in morphine-treated neurons, indicates a causal relationship between the reciprocal changes in G-protein number and the increase of dopamine D1 receptor-stimulated adenylyl cyclase activity. The possible role of these changes in G-protein number in the development of morphine tolerance and dependence is discussed.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2006

On the statistical analysis of the GS-NS0 cell proteome: imputation, clustering and variability testing.

We have undertaken two-dimensional gel electrophoresis proteomic profiling on a series of cell lines with different recombinant antibody production rates. Due to the nature of gel-based experiments not all protein spots are detected across all samples in an experiment, and hence datasets are invariably incomplete. New approaches are therefore required for the analysis of such graduated datasets. We approached this problem in two ways. Firstly, we applied a missing value imputation technique to calculate missing data points. Secondly, we combined a singular value decomposition based hierarchical clustering with the expression variability test to identify protein spots whose expression correlates with increased antibody production. The results have shown that while imputation of missing data was a useful method to improve the statistical analysis of such data sets, this was of limited use in differentiating between the samples investigated, and highlighted a small number of candidate proteins for further investigation.

Algorithms↗
PubMed2006

Epac- and Rap- independent ERK1/2 phosphorylation induced by Gs-coupled receptor stimulation in HEK293 cells.

Serotonin activates Ras and Ras-dependent ERK1/2 phosphorylation in HEK293 cells expressing G(s)-coupled 5-HT(4) or 5-HT(7) serotonin receptors through unknown mechanisms. Both Epac/Rap-dependent and -independent pathways for Ras-dependent ERK1/2 activation have been suggested. Epac overexpression or Epac-specific 8-CPT-2'-O-Me-cAMP did not cause ERK1/2 phosphorylation, despite Rap activation. The data did not support a role for PLCepsilon or DAG-dependent Ras GEFs of the Ras-GRP family in Ras-dependent ERK1/2 phosphorylation. However, serotonin stimulated phosphorylation of endogenous and recombinant Ras-GRF1, increased [Ca(2+)](i) and caused Ca(2+)- and calmodulin-dependent ERK1/2 phosphorylation. Different signalling pathways seem to be utilised by G(s)-coupled receptors in various isolates of HEK293 cells.

Calcium↗
PubMed1986

Evidence that thyrotropin-releasing hormone-induced increases in GTPase activity and phosphoinositide metabolism in GH3 cells are mediated by a guanine nucleotide-binding protein other than Gs or Gi.

Thyrotropin-releasing hormone (TRH), vasoactive intestinal polypeptide (VIP) and acetylcholine stimulated high affinity GTPase activity in GH3 cell membrane preparations. The effects of acetylcholine and VIP were blocked by pretreatment of cultured cells with pertussis toxin and cholera toxin respectively. Such pretreatment, which causes covalent modification of the guanine nucleotide-binding proteins (G-proteins) of adenylate cyclase, did not, however, block the effects of TRH on GTPase activity or phosphoinositide breakdown. These data suggest that TRH receptors interact with a G-protein discrete from those associated with regulation of adenylate cyclase activity.

Adenosine Diphosphate Ribose↗
PubMed1996

GS protein mutations and pituitary tumors: functional correlates and possible therapeutic implications.

In more than one third of growth hormone (GH)-secreting pituitary adenomas, a point mutation in the gene for the alpha-chain of the G stimulatory protein (gsp oncogene) causes the constitutive activation of the membrane adenylyl cyclase (AC) resulting in uncontrolled cyclic adenosine monophosphate (cAMP) elevation and GH hypersecretion. Tumors expressing gsp are characterized by high membrane AC activity, elevated intracellular cAMP content, and high rates of GH release in culture medium. The AC activity is not further stimulated by GH-releasing hormone (GHRH) and other specific and non-specific agents, while it is lowered by somatostatin, as the G inhibitory protein (Gi) is normally working. Acromegalic patients bearing adenomas with the gsp mutation do not present with any obvious clinical or epidemiological distinctive features. However, they have smaller tumors in relation to their circulating GH levels, suggesting that the gsp oncogene maintains a high rate of secretory activity in vivo. Most of these patients show paradoxical GH increases to thyrotropin-releasing hormone (TRH), but none to gonadotropin-releasing hormone (GnRH) or an oral glucose tolerance test (OGTT). As with the in vitro data, these patients are not very sensitive to GHRH administration, but are sensitive to the inhibitory action of somatostatin. In our experience, only three of six patients with non-gsp-mutated tumors had lowered serum GH levels during the administration of octreotide (100 micrograms thrice daily for 4 years), while all of six patients with gsp-mutated tumors had serum GH levels suppressed by octreotide treatment. Such a good GH suppressibility by somatostatin makes patients with gsp-mutated tumors the best candidates for medical treatment with somatostatin analogs.

Acromegaly↗
PubMedDate not supplied

Vitamin D(3) analogs (MC 1288, KH 1060, EB 1089, GS 1558, and CB 1093): studies on their mechanism of action.

Selected 20-epi and 20-normal vitamin D(3) analogs were studied. First, point mutations were introduced into human vitamin D receptor (VDR) to identify residues important for ligand binding. In helices three, four and five, His229, Asp232, Ser237 and Arg274 seem to have an important role in the binding of calcitriol. Surprisingly, the 20-epi analog MC 1288 did not bind to Ser237. Second, the effects of analogs on VDR degradation were studied. The transcriptionally active 20-epi analogs protected VDR against degradation more efficiently than the 20-normal analogs and calcitriol. With proteasome inhibitor MG-132 formation of Sug-1-RXRbeta-VDR-VDRE complex was detected. The 20-epi analogs effectively prevented its formation. Thus, the 20-epi analogs induce a VDR conformation, which prevents binding of factors mediating VDR degradation. Third, the analogs were found to be powerful regulators of cell cycle progression in MG-63 cells. They arrested cell cycle in the G0/G1 phase at lower concentrations and earlier time points than calcitriol. This was accompanied by hypophosphorylation of Rb followed by strong inhibition of Cdk2 activity. This correlated with increased levels of p27. Cdk2 and cyclin E levels were downregulated but those of p21 and cyclin D1 were not affected. Thus, a similar sequence of events with calcitriol and the analogs in inhibiting MG-63 cell growth was detected but the analogs had much longer lasting and stronger effects than calcitriol. A unifying scheme for the varying effects of vitamin D(3) analogs is presented.

Animals↗
PubMedDate not supplied

Fine tuning of glutamate uptake and degradation in glial cells: common transcriptional regulation of GLAST1 and GS.

Glutamate is the major excitatory neurotransmitter in the mammalian brain and retina, and glutamate uptake is essential for the normal function of glutamatergic synapses in the retina. As summarized here, all neuronal and macroglial cells of the retina express high-affinity glutamate transporters. GLAST1 is expressed in glial cells, whereas GLT1 and EAAC1 are neuronal. Glutamate uptake studies in intact retina revealed that Müller glial cells dominate the total retinal glutamate transport and that this uptake is strongly influenced by the activity of glutamine synthetase. A prerequisite for an effective glutamate-glutamine cycle in glial cells would be the regulated coordination between glutamate uptake and glutamate degradation. Using cultured retinal Müller glial cells, we demonstrate that protein expression of both, GLAST1 and glutamine synthetase, are inducible by the glucocorticoid hormone cortisol. These results suggest a common transcriptional regulation of the key proteins in the glial portion of the glutamate-glutamine cycle and may impact on transmitter clearance, transmitter recycling and, as discussed, on the development of the cellular architecture in retina.

ATP-Binding Cassette Transporters↗
PubMed1989

GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours.

A subset of growth hormone-secreting human pituitary tumours carries somatic mutations that inhibit GTPase activity of a G protein alpha chain, alpha(s). The resulting activation of adenylyl cyclase bypasses the cells' normal requirement for trophic hormone. Amino acids substituted in the putative gsp oncogene identify a domain of G protein alpha-chains required for intrinsic ability to hydrolyse GTP. This domain may serve as a built-in counter-part of the separate GTPase-activating proteins required for GTP hydrolysis by small GTP-binding proteins such as p21ras.

Adenylyl Cyclases↗