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PubMed2003

An estrogen-dependent four-gene micronet regulating social recognition: a study with oxytocin and estrogen receptor-alpha and -beta knockout mice.

Estrogens control many physiological and behavioral processes, some of which are connected to reproduction. These include sexual and other social behaviors. Here we implicate four gene products in a micronet required for mammalian social recognition, through which an individual learns to recognize other individuals. Female mice whose genes for the neuropeptide oxytocin (OT) or the estrogen receptor (ER)-beta or ER-alpha had been selectively "knocked out" were deficient specifically in social recognition and social anxiety. There was a remarkable parallelism among results from three separate gene knockouts. The data strongly suggest the involvement in social recognition of the four genes coding for ER-alpha, ER-beta, OT, and the OT receptor. We thus propose here a four-gene micronet, which links hypothalamic and limbic forebrain neurons in the estrogen control over the OT regulation of social recognition. In our model, estrogens act on the OT system at two levels: through ER-beta, they regulate the production of OT in the hypothalamic paraventricular nucleus, and through ER-alpha, they drive the transcription of the OT receptor in the amygdala. The proper operation of a social recognition mechanism allows for the expression of appropriate social behaviors, aggressive or affiliative.

Animals↗
PubMed2005

Chemically synthesized pathogen-associated molecular patterns increase the expression of peptidoglycan recognition proteins via toll-like receptors, NOD1 and NOD2 in human oral epithelial cells.

Peptidoglycan recognition proteins (PGRPs), a novel family of pattern recognition molecules (PRMs) in innate immunity conserved from insects to mammals, recognize bacterial cell wall peptidoglycan (PGN) and are suggested to act as anti-bacterial factors. In humans, four kinds of PGRPs (PGRP-L, -Ialpha, -Ibeta and -S) have been cloned and all four human PGRPs bind PGN. In this study, we examined the possible regulation of the expression of PGRPs in oral epithelial cells upon stimulation with chemically synthesized pathogen-associated molecular patterns (PAMPs) in bacterial cell surface components: Escherichia coli-type tryacyl lipopeptide (Pam3CSSNA), E. coli-type lipid A (LA-15-PP), diaminopimelic acid containing desmuramyl peptide (gamma-D-glutamyl-meso-DAP; iE-DAP), and muramyldipeptide (MDP). These synthetic PAMPs markedly upregulated the mRNA expression of the four PGRPs and cell surface expression of PGRP-Ialpha and -Ibeta, but did not induce either mRNA expression or secretion of inflammatory cytokines, in oral epithelial cells. Suppression of the expression of Toll-like receptor (TLR)2, TLR4, nucleotide-binding oligomerization domain (NOD)1 and NOD2 by RNA interference specifically inhibited the upregulation of PGRP mRNA expression induced by Pam3CSSNA, LA-15-PP, iE-DAP and MDP respectively. These PAMPs definitely activated nuclear factor (NF)-kappaB in the epithelial cells, and suppression of NF-kappaB activation clearly prevented the induction of PGRP mRNA expression induced by these PAMPs in the cells. These findings suggested that bacterial PAMPs induced the expression of PGRPs, but not proinflammatory cytokines, in oral epithelial cells, and the PGRPs might be involved in host defence against bacterial invasion without accompanying inflammatory responses.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2004

Comparisons between mammalian and artificial olfaction based on arrays of carbon black-polymer composite vapor detectors.

Arrays of broadly cross-reactive vapor sensors provide a man-made implementation of an olfactory system, in which an analyte elicits a response from many receptors and each receptor responds to a variety of analytes. Pattern recognition methods are then used to detect analytes based on the collective response of the sensor array. With the use of this architecture, arrays of chemically sensitive resistors made from composites of conductors and insulating organic polymers have been shown to robustly classify, identify, and quantify a diverse collection of organic vapors, even though no individual sensor responds selectively to a particular analyte. The properties and functioning of these arrays are inspired by advances in the understanding of biological olfaction, and in turn, evaluation of the performance of the man-made array provides suggestions regarding some of the fundamental odor detection principles of the mammalian olfactory system.

Animals↗
PubMed2003

Cellular recognition of tri-/di-palmitoylated peptides is independent from a domain encompassing the N-terminal seven leucine-rich repeat (LRR)/LRR-like motifs of TLR2.

Toll-like receptors (TLRs) mediate microbial pattern recognition in vertebrates. A broad variety of agonists has been attributed to TLR2 and three TLRs, TLR4, TLR2, and TLR5, have been demonstrated to bind microbial products. Distinct agonists might interact with different subdomains of the TLR2 extracellular domain. The TLR2 extracellular domain sequence includes 10 canonical leucine-rich repeat (LRR) motifs and 8-10 additional and potentially functionally relevant LRR-like motifs. Thus, the transfection of TLR2 LRR/LRR-like motif deletion constructs in human embryonic kidney 293 cells and primary TLR2-deficient mouse fibroblasts was performed for analysis of the role of the regarding domains in specific pattern recognition. Preparations applied as agonists were highly purified soluble peptidoglycan, lipoteichoic acid, outer surface protein A from Borrelia burgdorferi, synthetic mycoplasmal macrophage-activating lipoprotein-2, tripalmitoyl-cysteinyl-seryl-(lysyl)3-lysine (P3CSK4), dipalmitoyl-CSK4 (P2-CSK4), and monopalmitoyl-CSK4 (PCSK4) as well as lipopolysaccharide and inactivated bacteria. We found that a block of the N-terminal seven LRR/LRR-like motifs was not involved in TLR2-mediated cell activation by P3CSK4 and P2CSK4 ligands mimicking triacylated and diacylated bacterial polypeptides, respectively. In contrast, the integrity of the TLR2 holoprotein was compulsory for effective cellular recognition of other TLR2 agonists applied, including PCSK4. The formation of a functionally relevant subdomain by a region including the N-terminal seven LRR/LRR-like motifs rather than by single LRRs is suggested by our results. They further imply that TLR2 contains multiple binding domains for ligands that may contribute to the characterization of its promiscuous molecular pattern recognition.

Amino Acid Motifs↗
PubMed2002

Selective disruption of the recognition of facial expressions of anger.

Appetitive aggression occurs in the context of resource/dominance disputes in a wide variety of species. Hence, the possibility arises that a specific neural system may have evolved to detect and coordinate responses to this specific form of challenge or threat. The dopamine system has been implicated in the processing of signals of aggression in social-agonistic encounters in several species. Here we report that dopaminergic antagonism in healthy male volunteers, following acute administration of the dopamine D2-class receptor antagonist sulpiride, leads to a selective disruption in the recognition of facial expressions of anger (signals of appetitive aggression in humans), but leaves intact recognition of other emotions and the matching of unfamiliar faces.

Adult↗
PubMed2006

S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules.

Damage-associated molecular pattern (DAMP) molecules have been introduced as important proinflammatory factors of innate immunity. One example known for many years to be expressed in cells of myeloid origin are phagocytic S100 proteins, which mediate inflammatory responses and recruit inflammatory cells to sites of tissue damage. An emerging concept of pattern recognition involves the multiligand receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) in sensing not only pathogen-associated molecular patterns (PAMPs) but also endogenous DAMPs, including S100 proteins. S100A8, S100A9, and S100A12 are found at high concentrations in inflamed tissue, where neutrophils and monocytes belong to the most abundant cell types. They exhibit proinflammatory effects in vitro at concentrations found at sites of inflammation in vivo. Although S100A12 binds to RAGE, at least part of the proinflammatory effects of the S100A8/S100A9 complex depend upon interaction with other receptors. Because of the divergent expression patterns, the absence of S100A12 in rodents, the different interaction partners described, and the specific intracellular and extracellular effects reported for these proteins, it is important to differentiate between distinct S100 proteins rather than subsuming them with the term "S100/calgranulins." Analyzing the molecular basis of the specific effects exhibited by these proteins in greater detail bears the potential to elucidate important mechanisms of innate immunity, to establish valid biomarkers of phagocytic inflammation, and eventually to reveal novel targets for innovative anti-inflammatory therapies.

Animals↗
PubMed2006

The different effects on recognition memory of perirhinal kainate and NMDA glutamate receptor antagonism: implications for underlying plasticity mechanisms.

To investigate the involvement of different types of glutamate receptors in recognition memory, selective antagonists of NMDA and kainate receptors were locally infused into the perirhinal cortex of the rat temporal lobe. Such infusion of a selective kainate receptor antagonist produced an unusual pattern of recognition memory impairment: amnesia after a short (20 min) but not a long (24 h) delay. In contrast, antagonism of perirhinal NMDA glutamate receptors by locally infused AP-5 (2-amino-5-phosphonopentanoic acid) impaired recognition memory after the long but not the short delay. For both drugs, impairment was found when the drug was present during acquisition but not when it was present during retrieval. Experiments in vitro indicate that selective antagonism of NMDA receptors containing NR2A subunits blocks perirhinal long-term potentiation (LTP), whereas antagonism of NMDA receptors containing NR2B subunits blocks long-term depression (LTD). However, recognition memory after a 24 h delay was impaired only when both an NR2A and an NR2B antagonist were infused together, not when either was infused separately. These results establish that kainate receptors have a role in recognition memory that is distinct from that of NMDA receptors, that there must be at least two independent underlying memory mechanisms in the infused region, that this region and no other is necessary for both short-term and long-term familiarity discrimination, and that perirhinal-dependent long-term recognition memory does not rely solely on processes used in NMDA-dependent LTP or LTD (although it might be independently supported by components of each type of process with one substituting for the other).

Animals↗
PubMed2004

Four N-linked glycosylation sites in human toll-like receptor 2 cooperate to direct efficient biosynthesis and secretion.

Most higher organisms have a system of innate immune defense that is mediated by a group of evolutionarily related, germ line-encoded receptors, so-called Toll-like receptors. In mammals Toll-like receptors signal in response to pathogen-associated microbial structures. For example, Toll-like receptor 2 appears to mediate responses to bacterial peptidoglycan and acylated lipoproteins and Toll-like receptor 4 to bacterial lipopolysaccharide. However, the structural principles that underlie recognition of these structures are poorly understood. Toll-like receptors have leucine-rich repeats in their extracellular domains and are thus believed to adopt solenoid structures, similar to that found in platelet glycoprotein Ib. Additionally, all Toll-like receptors contain N-linked glycosylation consensus sites, and Toll-like receptor 4 requires glycosylation for function. Toll-like receptor glycosylation is also likely to influence receptor surface representation, trafficking, and pattern recognition. Using circular dichroism spectroscopy, we show here that purified human Toll-like receptor 2 and 4 proteins have secondary structure contents similar to glycoprotein Ib. We have also analyzed where consensus glycosylation sites are located in the extracellular domains of other human Toll-like receptors. We found that there are significant differences in the location and degree of conservation between sites in different Toll-like receptors. Using site-directed mutagenesis, we have found that in Toll-like receptor 2 extracellular domain all four predicted glycosylation sites are substituted, although one site is inefficiently core-glycosylated and its removal drastically affects secretion. The remaining Toll-like receptor 2 glycosylation sites also contribute to efficient protein secretion, albeit to a lesser degree.

Amino Acid Sequence↗
PubMed1994

Spatial frequency tuning of the monkey pattern ERG depends on D2 receptor-linked action of dopamine.

The pattern electroretinogram (PERG) has been previously shown to be sensitive to dopaminergic manipulations in the monkey's retina. In order to study the role of retinal D2 receptors were recorded the PERG before and during the acute administration of l-sulpiride, a selective D2 blocker, in three monkeys. The stimuli were sinusoidal vertical gratings, with a contrast of 70% counterphase modulated at 7.5 Hz. The response to four different spatial frequencies (0.5, 1.1, 2.3 and 4.6 c/deg) was explored. PERGs were recorded before and after 20 min of i.m. administration of l-sulpiride. Two different doses (0.07 and 0.35 mg/kg) were administered in different sessions for each spatial frequency (SF). Baseline (before sulpiride) responses showed high intersession reproducibility, with a clear SF tuning. Both doses of the drug affected the PERG to the peak SF of the stimulus, but the higher one was more consistently effective in all of the three monkeys. Our results confirm previous studies which suggested that DA is involved in retinal processing in the primate and reveal the new information that D2 receptors are necessary for spatio-temporal tuning of pattern vision.

Animals↗
PubMed1995

Evidence that the antigen receptors of cytotoxic T lymphocytes interact with a common recognition pattern on the H-2Kb molecule.

Recognition of class I MHC antigens involves interaction between TCRs of cytotoxic T lymphocytes (CTL) and the two alpha helices of MHC molecules. Using a combined panel of H-2Kb mutants selected by either a CTL clone or MAbs, we have shown evidence that the TCRs of 59 Kb-specific CTL clones shared a common binding pattern on the H-2Kb molecule. Mutations of amino acid residues at the C-terminal regions, but not the N-terminal regions, of the alpha helices abrogated the recognition by the majority of the clones. The data suggests that TCRs predominantly recognize the class I MHC molecule with an orientation that is parallel to the beta-pleated strands and diagonal to the alpha helices.

Animals↗
PubMed2006

Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia.

Influenza A virus (IAV) is the etiological agent of a highly contagious acute respiratory disease that causes epidemics and considerable mortality annually. Recently, we demonstrated, using an in vitro approach, that the pattern recognition Toll-like receptor (TLR)3 plays a key role in the immune response of lung epithelial cells to IAV. In view of these data and the fact that the functional role of TLR3 in vivo is still debated, we designed an investigation to better understand the role of TLR3 in the mechanisms of IAV pathogenesis and host immune response using an experimental murine model. The time-course of several dynamic parameters, including animal survival, respiratory suffering, viral clearance, leukocyte recruitment into the airspaces and secretion of critical inflammatory mediators, was compared in infected wild-type and TLR3(-/-) mice. First, we found that the pulmonary expression of TLR3 is constitutive and markedly upregulated following influenza infection in control mice. Notably, when compared to wild-type mice, infected TLR3-/- animals displayed significantly reduced inflammatory mediators, including RANTES (regulated upon activation, normal T cell expressed and secreted), interleukin-6, and interleukin-12p40/p70 as well as a lower number of CD8+ T lymphocytes in the bronchoalveolar airspace. More important, despite a higher viral production in the lungs, mice deficient in TLR3 had an unexpected survival advantage. Hence, to our knowledge, our findings show for the first time that TLR3-IAV interaction critically contributes to the debilitating effects of a detrimental host inflammatory response.

Acute Disease↗
PubMed2001

Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5.

BACKGROUND: The binding of neurotrophin ligands to their respective Trk cellular receptors initiates intracellular signals essential for the growth and survival of neurons. The site of neurotrophin binding has been located to the fifth extracellular domain of the Trk receptor, with this region regulating both the affinity and specificity of Trk receptor:neurotrophin interaction. Neurotrophin function has been implicated in a number of neurological disorders, including Alzheimer's disease and Parkinson's disease. RESULTS: We have determined the 2.7 A crystal structure of neurotrophin-4/5 bound to the neurotrophin binding domain of its high-affinity receptor TrkB (TrkB-d5). As previously seen in the interaction of nerve growth factor with TrkA, neurotrophin-4/5 forms a crosslink between two spatially distant receptor molecules. The contacts formed in the TrkB-d5:neurotrophin-4/5 complex can be divided into a conserved area similar to a region observed in the TrkA-d5:NGF complex and a second site-unique in each ligand-receptor pair-formed primarily by the ordering of the neurotrophin N terminus. CONCLUSIONS: Together, the structures of the TrkB-d5:NT-4/5 and TrkA-d5:NGF complexes confirm a consistent pattern of recognition in Trk receptor:neurotrophin complex formation. In both cases, the N terminus of the neurotrophin becomes ordered only on complex formation. This ordering appears to be directed largely by the receptor surface, with the resulting complementary surfaces providing the main determinant of receptor specificity. These features provide an explanation both for the limited crossreactivity observed between the range of neurotrophins and Trk receptors and for the high-affinity binding associated with respective ligand-receptor pairs.

Amino Acid Motifs↗
PubMed2006

The long pentraxin PTX3 in vascular pathology.

Pentraxins are a family of evolutionarily conserved multifunctional pattern-recognition proteins characterized by a cyclic multimeric structure. Based on the primary structure of the subunit, the pentraxins are divided into two groups: short pentraxins and long pentraxins. C-reactive protein (CRP) and serum amyloid P-component (SAP) are the two short pentraxins. The prototype protein of the long pentraxin group is pentraxin 3 (PTX3). CRP and SAP are produced primarily in the liver in response to IL-6, while PTX3 is produced by a variety of tissues and cells and in particular by innate immunity cells in response to proinflammatory signals and Toll-like receptor (TLR) engagement. PTX3 interacts with several ligands, including growth factors, extracellular matrix components and selected pathogens, playing a role in complement activation and facilitating pathogen recognition by phagocytes, acting as a predecessor of antibodies. In addition, PTX3 is essential in female fertility by acting as a nodal point for the assembly of the cumulus oophorus hyaluronan-rich extracellular matrix. Thus, the prototypic long pentraxin PTX3 is a multifunctional soluble pattern recognition receptor acting as a non-redundant component of the humoral arm of innate immunity and involved in tuning inflammation, in matrix deposition and female fertility.

Animals↗
PubMed1993

The constitution of a progesterone response element.

Progesterone receptors (PRs) recognize and bind to DNA in a sequence-specific manner. To define the sequence-specific determinants of PR binding to DNA, we employed a detailed series of target elements and analyzed both PR binding in vitro and PR-mediated activation of a reporter gene in vivo. These elements represent point substitution or insertion mutants of a progesterone response element derived from the mouse mammary tumor virus (MMTV). Substitution of a G for the first T in the 15-base pair (bp) MMTV progesterone response element core sequence, GTTACAAACTGTTCT, increases PR-DNA binding in vitro. All other tested mutations within this sequence either had no effect or decreased PR binding. From these analyses, we infer an optimal PR recognition sequence, -7RGNACANRNTGTNCY+7, composed of hexameric half-sites separated by precisely 3 bp and exhibiting dyad symmetry. Limited substitution of a suboptimal base for an optimal base, as in the wild type MMTV element, can be tolerated, but further suboptimal substitutions significantly decrease binding by PR. The identity of 1 bp within the hexameric half-site, position +/- 5, is unconstrained. Transition mutations, but not transversions, are permitted at position +/- 7. Here the hydrogen bond acceptor of the N-7 position of the purine ring may be involved in receptor recognition, since this feature is shared by the permitted substitutions. Insertion of a single base pair between the half-sites abolishes detectable binding, suggesting that the spatial orientation of the DNA binding domains of the monomeric receptor subunits are fixed by dimerization of the receptor. This pattern of sequence-specific recognition parallels that previously inferred for the glucocorticoid receptor, indicating that the two receptors may be unable to distinguish individual target sites. Each of the mutant response elements was also assessed for its ability to confer progestin responsiveness to a truncated MMTV promoter when introduced into a PR-containing cell line. Elements exhibiting strong receptor binding in vitro were fully inducible, whereas poorly inducible or uninducible elements displayed little or no recognition by receptor in vitro. However, some elements, though poorly bound in vitro, still activated transcription in vivo in response to hormone. In certain cases activation was as good as that seen with the wild type element. Further examination of in vitro receptor binding by this class of mutant elements using higher levels of baculovirus-expressed receptor revealed that many were indeed recognized by receptor, albeit with a lower affinity than the wild type sequence.(ABSTRACT TRUNCATED AT 400 WORDS)

Baculoviridae↗
PubMed2003

Receptor subtypes: species variations in secretin affect potency for pancreatic but not gastric secretion.

INTRODUCTION: Receptor subtypes can be distinguished by different actions of agonists on physiologic responses. In this study, we compared effects of four species variants of secretin (rat, porcine, canine, and human) on pancreatic secretion and gastrin-induced acid secretion in urethane-anesthetized rats. These secretins differ by one to three residues in position 14, 15, or 16 and were used to probe for the presence of different secretin receptor subtypes in the rat. METHODOLOGY: Pancreatic responses were measured in a two-point parallel line bioassay with porcine secretin (3 and 30 pmol/kg IV bolus) as standard. Inhibition of gastric acid secretion by each secretin (100 pmol/[kg x h]) was quantitated against a threshold dosage of gastrin-17 (200 pmol/[kg x h]), and percent inhibition of incremental acid responses was determined. RESULTS: Rat secretin was significantly more potent than other secretins for pancreatic secretion, in the order of rat > porcine > canine > human. The four secretins significantly inhibited gastrin-induced acid secretion by 37% to 49%, with no statistically significant differences among the forms. CONCLUSIONS: Stimulation of pancreatic secretion was influenced by species variations in secretin structure, but inhibition of gastric acid secretion was not. This finding suggests that secretin receptor subtypes with different recognition patterns mediate these responses.

Amino Acid Sequence↗
PubMed2005

Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors.

The molecular mechanisms contributing to the normal age-related decline of cognitive functions or to pathological learning and memory impairment are largely unknown. We demonstrate here that young mice (6-7 weeks) with a genetic deletion of the cannabinoid CB1 receptor performed as well as WT mice, or often better, in a number of learning and memory paradigms, including animal models of skill-learning, partner recognition, and operant conditioning. In contrast, the performance of mature mice (3-5 months) lacking CB1 receptors was much worse than that of age-matched WT animals. In most tests, these mice performed at the same level as old animals (14-17 months), suggesting that the decline in cognitive functions is accelerated in the absence of CB1 receptors. This rapid decline in CB1-deficient animals is accompanied by a loss of neurons in the CA1 and CA3 regions of the hippocampus.

Aging↗