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PubMed2000

Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome.

Recent research has emphasized the importance of the metabolic cluster, which includes glucose intolerance, dyslipidemia, and high blood pressure, as a strong predictor of the obesity-related morbidities and premature mortality. Fundamental to this association, commonly referred to as the metabolic syndrome, is the close interaction between abdominal fat patterning, total body adiposity, and insulin resistance. As the initial step in identifying major genetic loci influencing these phenotypes, we performed a genomewide scan by using a 10-centiMorgan map in 2,209 individuals distributed over 507 nuclear Caucasian families. Pedigree-based analysis using a variance components linkage model demonstrated a quantitative trait locus (QTL) on chromosome 3 (3q27) strongly linked to six traits representing these fundamental phenotypes [logarithm of odds (lod) scores ranged from 2.4 to 3.5]. This QTL exhibited possible epistatic interaction with a second QTL on chromosome 17 (17p12) strongly linked to plasma leptin levels (lod = 5.0). Situated at these epistatic QTLs are candidate genes likely to influence two biologic precursor pathways of the metabolic syndrome.

Blood Glucose↗

PubMed1999

Gating mechanism of the nuclear pore complex channel in isolated neonatal and adult mouse liver nuclei.

Several types of ionic channels on the outer membrane of the nuclear envelope communicate with the nuclear cisternae. These are distinct from nucleocytoplasmic pathways, the nuclear pores that span the double membrane of the envelope and are the route for RNA and protein traffic in the nucleus. Recent data indicate that the nuclear pores may also function as ion channels. The most probable candidate for nucleocytoplasmic ion flux is a 300-400 pS pathway observed in many nuclear preparations. Morphological and functional studies of nuclear envelope suggest a tight relationship between the large conductance channel and the pore complex. However, there is no direct evidence for gating of the nuclear pore or its ability to open and close as a conventional channel. This study shows that in liver nuclei isolated from newborn mouse, there is a substantial correspondence between the number of pores and the number of channels recorded during patch-clamp. This is not the case for adult nuclei. Although pore density is comparable, some nuclear cytoskeletal components, such as actin and nonmuscle myosin, show a significant increase in the adult preparation. Previous studies demonstrate the presence of these two proteins in association with the pore complex. Here we show that by using actin filament disrupter, we were able to increase the number of active channels in adult isolated nuclei. We suggest that a functional interaction between actin filaments and the nuclear pore complex could regulate nucleocytoplasmic permeability.

Animals↗

PubMed2003

Lidocaine enhances Galphai protein function.

BACKGROUND: Local anesthetics inhibit several G protein-coupled receptors by interaction with the Galphaq protein subunit. It is not known whether this effect on G protein function can be extrapolated to other classes of G proteins. The authors investigated interactions of lidocaine with the human adenosine 1 receptor (hA1R)-coupled signaling pathway. Activated A1Rs couple to adenylate cyclase via the pertussis toxin sensitive Galphai protein, thereby decreasing cyclic adenosine monophosphate formation. A1Rs are widely expressed and abundant in the spinal cord, brain, and heart. Interactions of LAs with the hA1R-coupled transduction cascade therefore might produce a broad range of clinically relevant effects. METHODS: The function of hA1Rs stably expressed in Chinese hamster ovary cells was determined with assays of cyclic adenosine monophosphate, receptor binding, and guanosine diphosphate/guanosine triphosphate gamma35S exchange by using reconstituted defined G protein subunits. Involvement of phosphodiesterase and Galphai was characterized by using the phosphodiesterase inhibitor rolipram and pertussis toxin, respectively. RESULTS: Lidocaine (10-9-10-1 M) had no significant effects on agonist or antagonist binding to the hA1R or on receptor-G protein interactions. However, cyclic adenosine monophosphate levels were reduced significantly to 50% by the LAs, even in the absence of an A1R agonist or presence of an A1R antagonist. This effect was unaffected by rolipram (10 mum), but abolished completely by pretreatment with pertussis toxin, which inactivates the Galphai protein. Therefore, the main target site for LAs in this pathway is located upstream from adenylate cyclase. CONCLUSIONS: Lidocaine potentiates Galphai-coupled A1R signaling by reducing cyclic adenosine monophosphate production. The study suggests an interaction site for LAs in a Galphai-coupled signaling pathway, with the Galphai protein representing the prime candidate. Taken together with previous results showing inhibitory LA interactions on the Galphaq protein subunit, the data in the current study support the hypothesis that specific G protein subunits represent alternative sites of LA action.

Anesthetics, Local↗

PubMedDate not supplied

New approaches to chemotherapy-induced nausea and vomiting: from neuropharmacology to clinical investigations.

Nausea and vomiting are considered to be among the most distressing consequences of cytotoxic chemotherapies. Currently, there are several novel 5-HT(3) receptor antagonists for the treatment of chemotherapy-induced nausea and vomiting (CINV), including ondansetron, granisetron, and dolasetron. These agents provide significant improvement in the management of acute emesis but are ineffective at preventing delayed emesis. In 2003, a new 5-HT(3) receptor antagonist, palonosetron HCL (Aloxi), was introduced to the U.S. market. Palonosetron was found to be effective in preventing delayed CINV. Indeed, palonosetron was the first and only 5-HT(3) receptor antagonist approved by the FDA for the prevention of both acute and delayed CINV. More recently, studies on the role of substance P in the emetic process led to the development of aprepitant (Emend) for the prevention of delayed emesis in combination with 5-HT(3) receptor antagonists. Despite these major advances, CINV remains uncontrolled in some patients. Current efforts are focused on treating refractory emesis and include both the clinical evaluation of compounds marketed for other indications and the preclinical evaluation of novel molecules targeting other transmitters in the emetic pathway. Ongoing work in pharmacogenomics has postulated several candidate genes that could be involved in emetic sensitivity and responsiveness to antiemetic therapy. Investigations into the pharmacogenomics of CINV may someday be able to aid in the identification of high risk patients and patients unlikely to respond to conventional therapies.

Antiemetics↗

PubMed2004

Genetic variations in the vitamin D receptor, androgen receptor and enzymes that regulate androgen metabolism.

PURPOSE: We review the current literature on genetic variations in the vitamin D receptor (VDR), androgen receptor (AR) and enzymes regulating androgen development. MATERIALS AND METHODS: A MEDLINE search was conducted to identify research investigating associations between polymorphisms in important regulatory genes that may indirectly affect cancer risk, with special regard to prostate cancer. RESULTS: Genes involved in androgen regulation, metabolism and their related pathways, and the vitamin D receptor are prime candidates for study of prostate cancer risk. Expression and nuclear activation of the VDR are necessary for the antiproliferative effects of 1alpha,25-dihydroxyvitamin D3 (calcitriol), which is involved in calcium and bone homeostasis. Several genetic variations have been identified in the VDR, and at least 1 VDR polymorphism appears to confer some predictability of prostate cancer risk in various ethnic cohorts. Interactions between the androgen receptor and circulating androgens have a major role in the development of normal and malignant prostate cells. CONCLUSIONS: Due to the relationship between the AR and prostatic growth, it has been proposed that polymorphisms within the AR may have a role in susceptibility to prostate cancer.

Calcitriol↗

PubMed2005

Forcing interactions as a genetic screen to identify proteins that exert a defined activity.

The interaction of proteins to form macromolecular complexes is the basis for most biological processes. Approaches have been described that employ artificial constructs to promote such complexes and assess the consequences. For example, a protein interaction scheme has been described that examines the effects of a specific phosphorylation event catalyzed by a protein kinase via the provision of an artificial protein binding interface between a modified version of the kinase and a single substrate. We have generalized this type of approach to form the basis for a genetic selection to identify proteins that exert an activity when recruited to a target protein. The assay uses the leucine zipper domains from the mammalian transcription factors Fos and Jun to force the interaction of two proteins. With a target protein fused to the Jun zipper and a library of open reading frames fused to the Fos zipper, we demonstrate this approach in yeast with both a selection to identify membrane-associated proteins and a selection to identify candidate components of the filamentous growth MAP kinase pathway.

Binding Sites↗

PubMed2002

A custom-built insulin resistance gene chip.

OBJECTIVES/AIM: Microarray (gene chip) technology offers a powerful new tool for analyzing the expression of large numbers of genes in many experimental samples. The aim of this study was to design, construct, and use a gene chip to measure the expression levels of key genes in metabolic pathways related to insulin resistance. METHODS: We selected genes that were implicated in the development of insulin resistance, including genes involved in insulin signaling; glucose uptake, oxidation, and storage; fat uptake, oxidation, and storage; cytoskeletal components; and transcription factors. The key regulatory genes in the pathways were identified, along with other recently identified candidate genes such as calpain-10. A total of 242 selected genes (including 32 internal control elements) were sequence-verified, purified, and arrayed on aldehyde-coated slides. RESULTS: Where more than 1 clone containing the gene of interest was available, we chose those containing the genes in the 5' orientation and an insert size of around 1.5 kb. Of the 262 clones purchased, 56 (21%) were found to contain sequences other than those expected. In addition, 2 (1%) did not grow under standard conditions and were assumed to be nonviable. In these cases, alternate clones containing the gene of interest were chosen as described above. The current version of the Insulin Resistance Gene Chip contains 210 genes of interest, plus 48 control elements. A full list of the genes is available at http://www.hbs.deakin.edu.au/mru/research/gene_chip_tech/genechip_three.htm/. CONCLUSIONS: The human Insulin Resistance Gene Chip that we have constructed will be a very useful tool for investigating variation in the expression of genes relevant to insulin resistance under various experimental conditions. Initially, the gene chip will be used in studies such as exercise interventions, fasting, euglycemic-hyperinsulinemic clamps, and administration of antidiabetic agents.

Base Sequence↗

PubMed1977

An estimate of the secondary spindle receptor afferent contribution to the stretch reflex in extensor muscles of the decerebrate cat.

1. Vibration or stretch of the medial gastrocnemius muscle in the decerebrate cat each caused a significant increase in the tension of a synergist, the lateral gastrocenmius. 2. Simultaneous vibration and stretch of the medial gastrocnemius resulted in a substantial increase of lateral gastrocnemius tension which was greater that that produced by medial gastrocnemius vibration alone. The size of this force increase was proportional to the amplitude of medial gastrocnemius stretch, for the limited range of amplitudes examined. 3. Since the discharge of the medial gastrocnemius I a afferent fibres was held constant by vibration, the additional tension in lateral gastrocnemius provoked by medial gastrocnemius stretch must have resulted from the activation of an excitatory pathway separate from the I a afferent system. The secondary spindle afferent pathway was considered to be the most likely candidate. 4. The contributions of the Ia afferents and the additional stretch induced excitation to the stretch reflex were compared. The Ia potency was calculated from the ration of tonic vibration reflex force and the vibration frequency. The total Ia contribution to the stretch reflex, which was estimated from the product of this ratio and the primary ending stretch sensitivity, seemed modest, and was consistently smaller than the proposed secondary contribution. 5. The medial gastrocnemius nerve was subjected to anodal blockade at a strength sufficient to eliminate Ia transmission. Under these conditions, the lateral gastrocnemius excitation produced by medial gastrocnemius stretch or vibration was largely eliminated. When lateral gastrocnemius vibration was superimposed, the excitatory effect of medial gastrocnemius stretch was partly restored suggesting that some central facilitation by group Ia afferents may be necessary for group II pexcitatory effects to be manifested. 6. Although the additional excitatory actions of medial gastrocnemius stretch were examined exclusively in a synergist, it is suggested that similar effects are likely to occur in the homonymous stretch reflex.

Animals↗

PubMed1993

Pulmonary stretch receptor afferents activate excitatory amino acid receptors in the nucleus tractus solitarii in rats.

1. The goal of the present study was to identify potential neurotransmitter candidates in the Breuer-Hering (BH) reflex pathway, specifically at synapses between the primary afferents and probable second-order neurones (pump cells) within the nucleus tractus solitarii (NTS). We hypothesized that if activation of specific receptors in the NTS is required for production of the BH reflex, then (1) injection of the receptor agonist(s) would mimic the reflex response (apnoea), (2) injection of appropriate antagonists would impair the apnoea produced by either lung inflation or agonist injection, and (3) second-order neurones in the pathway would be excited by either lung inflation or agonists while antagonists would prevent the response to either. 2. Studies were carried out either in spontaneously breathing or in paralysed, thoracotomized and ventilated rats in which either diaphragm EMG or phrenic nerve activity, expired CO2 concentration and arterial pressure were continuously monitored. The BH reflex was physiologically activated by inflating the lungs. 3. Pressure injections (0.03-15 pmol) of selective excitatory amino acid (EAA) receptor agonists, quisqualic acid (Quis) and N-methyl-D-aspartic acid (NMDA) into an area of the NTS shown previously to contain neurones required for production of the BH reflex produced dose-dependent apnoeas that mimicked the response to lung inflation. Injection of substance P (0.03-4 pmol) did not alter baseline respiratory pattern. 4. Injections of the EAA antagonists, kynurenic acid (Kyn; 0.6-240 pmol), 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX) or 6,7-dinitroquinoxaline-2,3-dione (DNQX) into the BH region of the NTS reversibly impaired the apnoea produced by lung inflation. All three antagonists reduced or abolished the apnoeas resulting from injection of Quis or NMDA, and slowed baseline respiratory frequency. In contrast, injections of the highly selective NMDA receptor antagonist, D-2-amino-5-phosphonovaleric acids (AP5), in doses sufficient to block the apnoeic response to NMDA, neither altered the reflex apnoea evoked by lung inflation nor the baseline respiratory pattern. 5. Pump cells located within the BH region were excited by pressure injections of the broad spectrum EAA agonist, DL-homocysteic acid (DLH). Kyn reversibly blocked the excitation of pump cells in response to either lung inflation or DLH injection. 6. These findings suggest that EAAs mediate primary afferent excitation of second-order neurones in the Breuer-Hering reflex pathway, primarily through the activation of non-NMDA EAA receptor subtypes.

Amino Acids↗

PubMed2002

Will the real LHC II kinase please step forward?

Many laboratories have searched for the protein kinase responsible for phosphorylation of the chloroplast light-harvesting complex of photosynthesis, LHC II. The LHC II kinase provides a vital link in a redox signaling pathway of ecological, developmental, and evolutionary significance. Various candidates for the LHC II kinase, some stronger than others, have come and gone. Recently, a family of three thylakoid-associated kinases (TAKs) has been identified and purified; they too catalyze in vitro phosphorylation of LHC II. The LHC II kinase is part of an integrated network of signal transduction to which input is provided by a number of environmental factors. The implications of understanding these processes stretch beyond the important, central question of how plants adapt their photosynthetic machinery to changing wavelengths of light.

Arabidopsis Proteins↗

PubMed2003

The molecular basis for adhesion-mediated suppression of reactive oxygen species generation by human neutrophils.

Human neutrophil adherence to ECMs induces an initial inhibition of stimulated reactive oxygen species (ROS) formation, followed by an enhanced phase of oxidant production. The initial integrin-mediated suppression of ROS constitutes a mechanism to prevent inappropriate tissue damage as leukocytes migrate to inflammatory sites. The Rac2 guanosine 5'-triphosphatase (GTPase) is a critical regulatory component of the phagocyte NADPH oxidase. We show that activation of Rac2 is inhibited in adherent neutrophils, correlating with inhibition of ROS formation. Conversely, NADPH oxidase components p47 and p67 assemble normally, suggesting a specific action of adhesion on the Rac2 molecular switch. Reconstitution with activated Rac2 restored rapid NADPH oxidase activation kinetics to adherent neutrophils, establishing that inhibition was due to defective Rac2 activity. We provide evidence that integrins inhibit Rac2 activation via a membrane-associated guanine nucleotide exchange factor, likely to be Vav1. Activation of Vav1, but not its upstream activator, Syk, is suppressed by cell adhesion. Vav1 activity is inhibited due to dephosphorylation of the regulatory Tyr174 via enhanced tyrosine phosphatase activity in adherent cells. These studies identify an integrin-mediated pathway in which Vav1 is as a strong candidate for the critical regulatory point in suppression of Rac2 activation and ROS generation during inflammatory responses.

Cell Adhesion↗

PubMed2006

Evolution of candidate transcriptional regulatory motifs since the human-chimpanzee divergence.

BACKGROUND: Despite the recent completion of the chimpanzee genome project, few functionally significant sequence differences between humans and chimpanzees have thus far been identified. Alteration in transcriptional regulatory mechanisms represents an important platform for evolutionary change, suggesting that a significant proportion of functional human-chimpanzee sequence differences may affect regulatory elements. RESULTS: To explore this hypothesis, we performed genome-wide identification of conserved candidate transcription-factor binding sites that have evolved since the divergence of humans and chimpanzees. Analysis of candidate transcription-factor binding sites conserved between mouse and chimpanzee yet absent in human indicated that loss of candidate transcription-factor binding sites in the human lineage was not random but instead correlated with the biologic functions of associated genes. CONCLUSION: Our data support the notion that changes in transcriptional regulation have contributed to the recent evolution of humans. Moreover, genes associated with mutated candidate transcription-factor binding sites highlight potential pathways underlying human-chimpanzee divergence.

Animals↗

PubMed2026

Genomic early growth mechanisms of two endangered Mexican spruces.

This study elucidated the genomic basis of family-level growth variance in the critically endangered endemic Mexican spruces Picea martinezii and P. mexicana by: (i) analyzing family- and population-level variations in seedling basal diameter and height after 12 months of growth under common garden conditions and seed weight as maternal provisioning trait; and (ii) identifying genomic loci (SNPs) associated with these traits. Despite limited sample sizes (77 and 74 families representing all known populations of both species), 32 and 10 outlier SNPs were identified yielding 17 and six annotated candidate genes in P. martinezii and P. mexicana, respectively. These genes showed contrasting multivariate associations suggesting species-specific hypothesized growth strategies at the family level: defense-oriented framework in P. martinezii and plasticity-driven response in P. mexicana. Notably, several candidate genes encode key components of growth hormone pathways, including a gibberellin-regulated protein, a cytokinin hydroxylase and the AP2-like transcription factor ANT, providing valuable insights into how maternal genetic variation corresponds to the hormonal pathways that govern cell proliferation and organ size in the progeny. Integration of these findings with the contrasting demographic histories of both species revealed that population bottlenecks enhance the detectability of growth-associated variants by reducing background genetic variation. These genomic resources provide actionable information for prioritizing conservation measures, implementing assisted gene flow to maintain adaptive potential under climate change and designing future breeding programs. With 80.9-99.6% sequence identity to conserved Picea abies homologs, these findings may extend across the genus.

Picea↗

PubMed1995

[Biophysical and pharmacological characterization of receptor-operated nonselective cation channels (ROCC) and their regulatory mechanisms in smooth muscle].

Stimulation of excitatory receptors in smooth muscle often leads to the opening of ROCC. These channels exhibit considerable permeability to Ca2+, and they have been regarded as the most probable candidate for the "receptor-operated Ca2+ entry" pathway. The muscarinic receptor ROCC in guinea pig ileum (mROCC) have a unitary conductance of -25pS and are activated through a pertussis toxin-sensitive G protein. mROCC permeate Ca2+ and Ba2+ several fold more preferably than monovalent cations, and they are inhibited by various types of K channel blockers, diphenylamine-2-carboxylate derivatives and even by nicardipine and D-600 at high concentrations. mROCC are efficiently regulated by various physiological factors including the membrane potential, intracellular Ca2+ concentration, external pH and osmolarity. The effective ranges of these factors span their dynamic ranges under physiological conditions. In addition to these properties, mROCC have several sites sensitive to external polyvalent cations. The alpha 1-adrenergic receptor ROCC in rabbit portal vein resemble mROCC in many respects, e.g., the unitary conductance, ionic selectivity, activation kinetics, sensitivity to polyvalent cations and voltage-dependence. These complex characteristics of ROCC suggest that they play other roles in addition to being just a passive cation permeable pore in agonist-mediated Ca2+ mobilization in smooth muscle.

Animals↗

PubMed2002

Localization of the mutation responsible for osteopetrosis in the op rat to a 1.5-cM genetic interval on rat chromosome 10: identification of positional candidate genes by radiation hybrid mapping.

Osteopetrosis is caused by a heterogenous group of bone diseases that result in an increase in skeletal mass because of inadequate osteoclastic bone resorption. In the op osteopetrotic rat, the disease has been linked to a single genetic locus located at the proximal end of rat chromosome 10. In this study, we identified a 1.5-cM genetic interval that contains the mutation. We then generated an improved radiation hybrid (RH) map of this region to identify potential functional and positional candidates for the op gene. Using the rat genome radiation hybrid panel, we mapped 57 markers including 24 genes (14 that have not yet been mapped in the rat) and 10 expressed sequence tag markers. Included in the mapped genes are several candidate genes that might significantly influence the biochemical pathways involved in osteopetrosis. These include genes involved in osteoclast differentiation, apoptosis, and the functional capabilities of mature osteoclasts to resorb bone. Further analysis of the genes and expressed transcripts mapped to this region may yield important insights into the multifactorial control of osteoclast function and the mechanisms of failed bone homeostasis in diseases such as osteopetrosis, osteoporosis, and rheumatoid arthritis in which failed bone homeostasis is an instigating or exacerbating circumstance of the disease process.

Animals↗

PubMed2003

Deficient tumor necrosis factor-alpha production in lipoarabinomannan activated macrophages from toll-like receptor-4 deficient mice: implication for mycobacterial susceptibility.

Mice with a point mutation of toll-like receptor-4 (TLR-4) (C3H/HeJ) are hypo-responsive to LPS and more susceptible to mycobacterial infections than their control wild type (C3H/OuJ). We have previously shown that TLR-4-deficient mice produced NO in response to the mycobacterial product, ara-lipoarabinomannan (LAM), in the presence of either Interferon-beta (IFN-beta) or Interferon-gamma (IFN-gamma), with a dose response curve that produced levels of NO almost as high as those observed in C3H/OuJ mice at high concentrations of ara-LAM plus either IFN-beta or-gamma. We now report that tumor necrosis factor-alpha (TNF-alpha), an important cytokine for intracellular killing of mycobacteria, remains deficient in these C3H/HeJ mice compared to C3H/OuJ mice even at a high concentration of ara-LAM with either IFN-gamma or IFN-beta. In addition, TNF-alpha was further down regulated by taurine chloramine (Tau-Cl) in C3H/OuJ mice. The low level of TNF-alpha produced in the TLR-4-deficient (C3H/HeJ) mice was also further down regulated by Tau-Cl. These findings implicate the TLR-4 as an additional candidate locus for mycobacterial susceptibility, and provide a pathway for better understanding the molecular basis of this locus in the immunopathogenesis of mycobacterial infection.

Animals↗

PubMed2006

Low-density lipoprotein receptor-related protein 5 and vitamin D receptor gene polymorphisms in relation to vitamin D levels in menopause.

BACKGROUND: The low-density lipoprotein receptor-related protein 5 (LRP5) gene has been recently identified as a novel candidate for osteoporosis. The c.4037C>T polymorphism in the LRP5 gene has been associated with bone mass variance in general population. In contrast, the IVS8+443G>A polymorphism in the vitamin D receptor gene (VDR) has not been investigated in relation to bone metabolism. The aim of the present study was to determine VDR IVS8+443G>A and LRP5 c.4037C>T polymorphisms in a cohort of 165 perimenopausal women and to associate the genotypes with biochemical and densitometric bone parameters in a subset of 112 postmenopausal women. METHODS: Both polymorphisms were assessed by restriction analysis of the PCR product. Calcium, parathyroid hormone, vitamin D metabolites and bone mineral density (BMD, g/cm(2)) at the hip and in the spine (L(1)-L(4)) were examined. RESULTS: The genotype frequencies of both IVS8+443G>A (UU 75.2%, Uu 23%, uu 1.8%) and c.4037C>T (CC 73.9% TC 23.6%, TT 2.4%) were comparable to other Caucasian female cohorts. Serum 25OH vitamin D levels, assessed in only 63 probands, were significantly associated with VDR genotypes (ANCOVA, p A polymorphism was significantly associated with circulating 25OH vitamin D in postmenopausal Caucasian women. The role of candidate gene polymorphisms in the vitamin D metabolic pathway requires further investigation.

Aged↗

PubMed2004

Extracellular signal-regulated protein kinase activation is required for metabotropic glutamate receptor-dependent long-term depression in hippocampal area CA1.

Activation of group 1 metabotropic glutamate receptors (mGluRs) induces long-term depression (LTD) of synaptic transmission that relies on dendritic protein synthesis. We investigated the signal transduction pathways required for mGluR-LTD to identify candidate mechanisms for mGluR regulation of synaptic protein synthesis. Our results demonstrate a role for extracellular signal-regulated protein kinase (ERK), a subclass of the mitogen-activated protein kinases (MAPKs), in mGluR-LTD in area CA1 of the rat hippocampus. Inhibitors of the upstream kinase of ERK, MAP/ERK kinase significantly reduce mGluR-LTD induced by the group 1 agonist dihydroxyphenylglycine (DHPG) and synaptic stimulation but do not affect NMDA receptor-dependent LTD. In contrast, inhibitors of p38 MAPK were ineffective against DHPG-induced LTD. Consistent with the role of ERK in mGluR-LTD, we observed that DHPG treatment of hippocampal slices (isolated CA1), at concentrations that induce LTD, results in a robust phosphorylation of ERK but not of p38 MAPK. These results point to ERK as an important regulator of mGluR-LTD and a potential mechanism for mGluR regulation of synaptic protein synthesis.

Animals↗