PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 11435935

Decrease of adenylyl cyclase activity and expression by a sigma1 receptor ligand and putative atypical antipsychotic.

X Monroy·G Romero·M P Pérez·A J Farré·X Guitart
View original source ↗Export metadata ↓

Abstract

We examined whether changes in the adenylyl cyclase system could be induced by the administration of the sigma1 receptor ligand and putative atypical antipsychotic 4-[4-fluorophenyl]-1,2,3,6-tetrahydro-1-[4-[1,-2,4-triazol-1-il]butyl]pyridine citrate) (E-5842). Repeated (21 days) but not acute (2 h) treatment with E-5842 induced a significant decrease in adenylyl cyclase type I immunoreactivity and adenylyl cyclase activity in rat frontal cortex membranes, with less or no effect in other brain regions such as the hippocampus or the striatum. Changes in immunoreactivity were not observed in other adenylyl cyclases (type V/VI). The reported changes, observed only after a chronic treatment, could be related to the mechanism of action of sigma receptor ligands in general or to that of E-5842 in particular and should be taken into account, given the long duration of treatment in psychiatric patients.

Explore related subjects

Adenylyl CyclasesAnimalsAntipsychotic AgentsBrainCell MembraneColforsinCyclic AMPDown-RegulationFrontal LobeHippocampusLigandsMaleNeostriatumPyridinesRatsRats, WistarReceptors, sigmaSignal TransductionSubcellular FractionsTriazolesJournal Article

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

X Monroy, G Romero, M P Pérez, A J Farré, X Guitart. 2001-07-03. Decrease of adenylyl cyclase activity and expression by a sigma1 receptor ligand and putative atypical antipsychotic.. https://doi.org/10.1097/00001756-200107030-00042

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2004

Use of a dense single nucleotide polymorphism map for in silico mapping in the mouse.

Rapid expansion of available data, both phenotypic and genotypic, for multiple strains of mice has enabled the development of new methods to interrogate the mouse genome for functional genetic perturbations. In silico mapping provides an expedient way to associate the natural diversity of phenotypic traits with ancestrally inherited polymorphisms for the purpose of dissecting genetic traits. In mouse, the current single nucleotide polymorphism (SNP) data have lacked the density across the genome and coverage of enough strains to properly achieve this goal. To remedy this, 470,407 allele calls were produced for 10,990 evenly spaced SNP loci across 48 inbred mouse strains. Use of the SNP set with statistical models that considered unique patterns within blocks of three SNPs as an inferred haplotype could successfully map known single gene traits and a cloned quantitative trait gene. Application of this method to high-density lipoprotein and gallstone phenotypes reproduced previously characterized quantitative trait loci (QTL). The inferred haplotype data also facilitates the refinement of QTL regions such that candidate genes can be more easily identified and characterized as shown for adenylate cyclase 7.

Adenylyl Cyclases↗
PubMed2002

Adolescent nicotine administration alters serotonin receptors and cell signaling mediated through adenylyl cyclase.

Nicotine is a neuroteratogen that targets synaptic function during critical developmental stages and recent studies indicate that CNS vulnerability extends into adolescence, the age at which smoking typically commences. We administered nicotine to adolescent rats via continuous minipump infusions from PN30 to PN47.5, using 6 mg/kg/day, a dose rate that replicates the plasma nicotine levels found in smokers, and examined 5HT receptors and related cell signaling during nicotine administration (PN45) and in the post-treatment period (PN50, 60, 75). Adolescent nicotine decreased 5HT(2) receptor binding in brain regions containing 5HT projections (hippocampus and cerebral cortex), with selectivity for females in the cerebral cortex; regions containing 5HT cell bodies showed either an increase (midbrain in males) or no change (brainstem). In contrast, there were no significant changes in 5HT(1A) receptors; however, the ability of the receptors to signal through adenylyl cyclase (AC) showed a switch from stimulatory to inhibitory effects in females during the post-treatment period. There were also transient alterations in AC responses to beta-adrenergic receptor stimulation, as well as pronounced induction of the AC response to the non-receptor-mediated stimulant, forskolin. Our results indicate that adolescent nicotine exposure alters the concentrations and functions of postsynaptic 5HT receptors in a manner commensurate with impaired 5HT synaptic function. The direction of change, emergence of defects after the cessation of nicotine administration, and sex-preference for effects in females, all support a relationship of impaired 5HT function to the higher incidence of depression seen in adolescent smokers.

Adenylyl Cyclases↗
PubMed2002

G protein-coupled receptors form stable complexes with inwardly rectifying potassium channels and adenylyl cyclase.

A large number of studies have demonstrated co-purification or co-immunoprecipitation of receptors with G proteins. We have begun to look for the presence of effector molecules in these receptor complexes. Co-expression of different channel and receptor permutations in COS-7 and HEK 293 cells in combination with co-immunoprecipitation experiments established that the dopamine D(2) and D(4), and beta(2)-adrenergic receptors (beta(2)-AR) form stable complexes with Kir3 channels. The D(4)/Kir3 and D(2) receptor/Kir3 interaction does not occur when the channel and receptor are expressed separately and mixed prior to immunoprecipitation, indicating that the interaction is not an artifact of the experimental protocol and reflects a biosynthetic event. The observed complexes are stable in that they are not disrupted by receptor activation or modulation of G protein alpha subunit function. However, using a peptide that binds Gbetagamma (betaARKct), we show that Gbetagamma is critical for dopamine receptor-Kir3 complex formation, but not for maintenance of the complex. We also provide evidence that Kir3 channels and another effector, adenylyl cyclase, are stably associated with the beta(2)-adrenergic receptor and can be co-immunoprecipitated by anti-receptor antibodies. Using bioluminescence resonance energy transfer, we have shown that in living cells under physiological conditions, beta(2)AR interacts directly with Kir3.1/3.4 and Kir3.1/3.2c heterotetramers as well as with adenylyl cyclase. All of these interactions are stable in the presence of receptor agonists, suggesting that these signaling complexes persist during signal transduction. In addition, we provide evidence that the receptor-effector complexes are also found in vivo. The observation that several G protein-coupled receptors form stable complexes with their effectors suggests that this arrangement might be a general feature of G protein-coupled signal transduction.

Adenylyl Cyclases↗