Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
FEMS Microbiol Ecol ; 99(11)2023 10 17.
Article in English | MEDLINE | ID: mdl-37827541

ABSTRACT

Important bacterial pathogens such as Pseudomonas aeruginosa produce several exoproducts such as siderophores, degradative enzymes, biosurfactants, and exopolysaccharides that are used extracellularly, benefiting all members of the population, hence being public goods. Since the production of public goods is a cooperative trait, it is in principle susceptible to cheating by individuals in the population who do not invest in their production, but use their benefits, hence increasing their fitness at the expense of the cooperators' fitness. Among the most studied virulence factors susceptible to cheating are siderophores and exoproteases, with several studies in vitro and some in animal infection models. In addition to these two well-known examples, cheating with other virulence factors such as exopolysaccharides, biosurfactants, eDNA production, secretion systems, and biofilm formation has also been studied. In this review, we discuss the evidence of the susceptibility of each of those virulence factors to cheating, as well as the mechanisms that counteract this behavior and the possible consequences for bacterial virulence.


Subject(s)
Siderophores , Virulence Factors , Humans , Virulence Factors/genetics , Pseudomonas aeruginosa/genetics , Biofilms , Quorum Sensing
2.
Pharmacol Res ; 99: 174-84, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26116441

ABSTRACT

The dopamine D3 receptor exhibits agonist-dependent tolerance and slow response termination (SRT) signaling properties that distinguish it from the closely-related D2 receptors. While amino acid residues important for D3 receptor ligand binding have been identified, the residues involved in activation of D3 receptor signaling and induction of signaling properties have not been determined. In this paper, we used cis and trans isomers of a novel D3 receptor agonist, 8-OH-PBZI, and site-directed mutagenesis to identify key residues involved in D3 receptor signaling function. Our results show that trans-8-OH-PBZI, but not cis-8-OH-PBZI, elicit the D3 receptor tolerance and SRT properties. We show that while both agonists require a subset of residues in the orthosteric binding site of D3 receptors for activation of the receptor, the ability of the two isomers to differentially induce tolerance and SRT is mediated by interactions with specific residues in the sixth transmembrane helix and third extracellular loop of the D3 receptor. We also show that unlike cis-8-OH-PBZI, which is a partial agonist at the dopamine D2S receptor and full agonist at dopamine D2L receptor, trans-8-OH-PBZI is a full agonist at both D2S and D2L receptors. The different effect of the two isomers on D3 receptor signaling properties and D2S receptor activation correlated with differential effects of the isomers on agonist-induced mouse locomotor activity. The two isomers of 8-OH-PBZI represent novel pharmacological tools for in silico D3 and D2 receptor homology modeling and for determining the role of D3 receptor tolerance and SRT properties in signaling and behavior.


Subject(s)
Receptors, Dopamine D3/chemistry , Receptors, Dopamine D3/metabolism , Amino Acid Sequence , Amino Acid Substitution , Animals , Binding Sites/genetics , Cell Line , Dopamine Agonists/chemistry , Dopamine Agonists/pharmacology , Humans , Indoles/chemistry , Indoles/pharmacology , Male , Mice , Mice, Transgenic , Models, Molecular , Molecular Sequence Data , Motor Activity/drug effects , Mutagenesis, Site-Directed , Protein Conformation , Receptors, Dopamine D3/genetics , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Signal Transduction/drug effects , Stereoisomerism , Tetrahydronaphthalenes/pharmacology
3.
ACS Chem Neurosci ; 4(6): 940-51, 2013 Jun 19.
Article in English | MEDLINE | ID: mdl-23477444

ABSTRACT

The D3 dopamine receptor is a therapeutic target for treating various nervous system disorders such as schizophrenia, Parkinson's disease, depression, and addictive behaviors. The crystal structure of the D3 receptor bound to an antagonist was recently described; however, the structural features that contribute to agonist-induced conformational changes and signaling properties are not well understood. We have previously described the conformation-dependent tolerance and slow response termination (SRT) signaling properties of the D3 receptor and identified the C147 residue in the second intracellular loop (IL2) of the D3 receptor as important for the tolerance property. Interestingly, while IL2 and the C147 residue, in particular, were important for dopamine- and quinpirole-induced tolerance, this residue did not affect the severe tolerance induced by the high affinity, D3 receptor-selective agonist, PD128907. Here, we used D2/D3 receptor chimeras and site-specific D3 receptor mutants to identify another residue, D187, in the second extracellular loop (EC2) of the human D3 receptor that mediates the tolerance property induced by PD128907, quinpirole, pramipexole, and dopamine. Molecular dynamics simulations confirmed the distinct conformation adopted by D3 receptor during tolerance and suggested that in the tolerant D3 receptor the D187 residue in EC2 forms a salt bridge with the H354 residue in EC3. Indeed, site-directed mutation of the H354 residue resulted in loss of PD1287907-induced tolerance. The mapping of specific amino acid residues that contribute to agonist-dependent conformation changes and D3 receptor signaling properties refines the agonist-bound D3 receptor pharmacophore model which will help develop novel D3 receptor agonists.


Subject(s)
Dopamine Agonists/pharmacology , Drug Tolerance/physiology , Extracellular Fluid/physiology , Receptors, Dopamine D3/agonists , Receptors, Dopamine D3/genetics , Amino Acid Sequence , Animals , Benzopyrans/pharmacology , Cells, Cultured , Humans , Mice , Oxazines/pharmacology , Protein Structure, Secondary , Receptors, Dopamine D3/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL
...