Biomedical subjects

A Rodríguez-Moreno

Publications and source records attributed to A Rodríguez-Moreno.

9 recordsLinked to original sources

PubMed2005

Association of the genetic polymorphisms of the renin-angiotensin system with kidney graft long-term outcome: preliminary results.

Recent studies have demonstrated some association between the renin-angiotensin system (RAS) activity and the development and progression of different entities as diabetes mellitus (DM) or chronic allograft nephropathy. To investigate these associations, we studied some gene polymorphisms of RAS in a group of renal transplant recipients. We retrospectively analyzed 42 patients who underwent a primary renal transplantation for 2 years. A subgroup of 23 patients (55%) was diagnosed with postransplant DM in accordance with American Diabetes Association 2001 criteria. We studied two RAS gene polymorphisms: the angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensinogen (AGTM235T). Genotyping was performed by DNA purification and amplification with a polymerase chain reaction technique. The distributions of genotypes were ACE DD, ID, II: 33%, 48%, 19%; and AGT TT, MT, MM: 15%, 45%, 40%, respectively. We observed a progressive loss in renal function measured by creatinine clearance (Cockroft) in D-allele carriers (DD+ID) between the first and the second transplantation year: 65.3 +/- 4.3 vs 59.8 +/- 4.6 mL/min (P = 0.02); that was not seen in II patients: 68.8 +/- 4.6 vs 68.4 +/- 4 mL/min (P = 0.87). Fifty percent of D-allele carriers developed DM vs 25% of non-D-allele carriers (P = 0.19). Eighty-three percent of homozygous patients for the AGT-TT allele developed DM vs 35% of non TT patients (P = 0.04). There were no significant differences regarding recipient demographic characteristics, type of donor, number and severity of acute rejections, and immunosuppressant treatment between the groups. In conclusion, ACE D-allele seems to be associated with a poorer kidney graft long-term outcome. ACE D and AGT T alleles may be implicated in glucose metabolism disorders after transplantation.

DNA↗

PubMed2001

Molecular physiology of kainate receptors.

A decade ago, our understanding of the molecular properties of kainate receptors and their involvement in synaptic physiology was essentially null. A plethora of recent studies has altered this situation profoundly such that kainate receptors are now regarded as key players in the modulation of transmitter release, as important mediators of the postsynaptic actions of glutamate, and as possible targets for the development of antiepileptic and analgesic drugs. In this review, we summarize our current knowledge of the properties of kainate receptors focusing on four key issues: 1) their structural and biophysical features, 2) the important progress in their pharmacological characterization, 3) their pre- and postsynaptic mechanisms of action, and 4) their involvement in a series of physiological and pathological processes. Finally, although significant progress has been made toward the elucidation of their importance for brain function, kainate receptors remain largely an enigma and, therefore, we propose some new roads that should be explored to obtain a deeper understanding of this young, but intriguing, class of proteins.

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PubMed2000

Two populations of kainate receptors with separate signaling mechanisms in hippocampal interneurons.

Consistent with the epileptogenic and deleterious effects of the potent neurotoxin kainate, the activation of kainate receptors reduces the synaptic inhibition induced by the amino acid gamma-aminobutyric acid (GABA). Extrapolating from these data led to the conclusion that kainate receptors are located presynaptically. However, kainate directly depolarizes the inhibitory interneurons, causing them to fire repeatedly. This effect might indirectly decrease the size of inhibitory postsynaptic currents recorded from pyramidal cells and places in doubt the presynaptic location for kainate receptors. Here we show that both effects, membrane depolarization and the reduction of inhibitory potentials, can be dissociated by several means, particularly by the natural agonist of kainate receptors, glutamate. Indeed, when applied at low concentrations, glutamate inhibited GABA release without affecting the firing rate of GABA interneurons. These results indicate that CA1 interneurons contain two populations of kainate receptors, each with different agonist sensitivity and coupled to distinct signaling pathways.

2-Amino-5-phosphonovalerate↗

PubMed1998

Kainate receptor modulation of GABA release involves a metabotropic function.

The mechanism through which kainate receptors downregulate the release of GABA in the hippocampus is not known. We have found that the action of kainate on the hippocampal inhibitory postsynaptic current (IPSC) is mediated by a metabotropic process that is sensitive to Pertussis toxin (PTx) and independent of ion channel current. The downregulation of GABA IPSCs by kainate was also prevented in a dose-dependent manner by calphostin C, a specific inhibitor of PKC, and the inhibition of phospholipase C (PLC) drastically reduced the action of kainate. The effect of kainate was completely occluded by phorbol esters and by increasing extracellular Ca2+ but remained unaltered after inhibition or activation of protein kinase A (PKA). These results demonstrate that the activation of kainate receptors triggers a second messenger cascade, which results in the stimulation of PKC, and therefore document a metabotropic action of kainate receptors, which results in the inhibition of GABA release.

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PubMed1998

Switch from facilitation to inhibition of excitatory synaptic transmission by group I mGluR desensitization.

We have explored whether the desensitization of metabotropic glutamate receptors (mGluRs) coupled to phosphoinositide hydrolysis affects the role that they play in modulating glutamate release. In hippocampal nerve terminals, the agonist 3,5-dihydroxyphenylglycine (DHPG) facilitated evoked glutamate release, but a second stimulation 5 min later reduced rather than facilitated release. After a 30 min interval between stimulations, DHPG again facilitated glutamate release. In hippocampal slices, DHPG caused an inhibition of excitatory postsynaptic currents (EPSCs) recorded from CA1 neurons. However, when the effects of ambient glutamate were prevented, mGluR activation initially induced a facilitation of synaptic transmission, followed by an inhibition. We conclude that group I mGluRs have a dual action on glutamate release, switching from facilitatory to inhibitory upon receptor desensitization triggered by low concentrations of glutamate.

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PubMed1997

Kainate receptors presynaptically downregulate GABAergic inhibition in the rat hippocampus.

Using microcultured neurons and hippocampal slices, we found that under conditions that completely block AMPA receptors, kainate induces a reduction in the effectiveness of GABAergic synaptic inhibition. Evoked inhibitory postsynaptic currents (IPSCs) were decreased by kainate by up to 90%, showing a bell-shaped dose-response curve similar to that of native kainate-selective receptors. The down-regulation of GABAergic inhibition was not affected by antagonism of metabotropic receptors, while it was attenuated by CNQX. Kainate increased synaptic failures and reduced the frequency of miniature IPSCs, indicating a presynaptic locus of action. In vivo experiments using brain dialysis demonstrated that kainate reversibly abolished recurrent inhibition and induced an epileptic-like electroencephalogram (EEG) activity. These results indicate that kainate receptor activation down-regulates GABAergic inhibition by modulating the reliability of GABA synapses.

2-Amino-5-phosphonovalerate↗

PubMedDate not supplied

Activation and desensitization properties of native and recombinant kainate receptors.

The activation-inactivation properties of membrane currents induced by the rapid application of glutamate or kainate were studied in cultured hippocampal neurons and in HEK cells transfected with a cDNA encoding the GluR6 subunit. The onset of desensitization was rapid and similar in native and recombinant channels (approximately 80 s(-1) of onset rate constant). Recovery from desensitization was slow and agonist-dependent in neurons, proceeding slightly faster in GluR6 receptors. Half-maximal activation (EC50) of native channels was obtained at a glutamate concentration of 330 microM, while the half-maximal steady state desensitization (IC1/2) was attained at 2.8 microM. These values differed from those obtained in recombinant receptors (EC50 = 762 microM and IC1/2 = 0.44 microM). A small window under the crossing point of activation and inactivation curves was observed, indicating that, for some concentrations of either agonist, steady state channel activity could exist. In native receptors, this window presented maximum values at approximately 100 microM for glutamate, which predicted well the potency of glutamate to reduce the GABAergic drive in hippocampal slices. These data indicate that for neuronal kainate receptors, the concentrations for half activation and half inactivation differ by two orders of magnitude such that the maximum response to a maintained concentration of glutamate is small, and the steady state dose response curve is skewed and bell shaped.

Animals↗

PubMedDate not supplied

[Kainate receptors. Their function in the regulation of GABAergic synaptic transmission in the hippocampus].

AIMS: The aim of this study is to describe the current state of knowledge about the physiology of kainate type glutamate receptors as modulators of GABAergic synaptic transmission in the hippocampus. DEVELOPMENT: The activation of kainate receptors (KR) located in the presynaptic terminal of the interneurons reduces GABAergic synaptic transmission at the interneuron principal cell synapse in the CA1 layer of the hippocampus. This diminished release of GABA involves a metabotropic effect, and an that activation of both a pertussis toxin sensitive G protein and protein kinase C is required. In these same interneurons there is also a population of KR with an ionotropic effect in the somatodendritic compartment, which depolarise them and give rise to a massive release of neurotransmitter when activated. It has very recently been shown that activating KR by submicromolar concentrations of agonist can bring about an increase in the release of GABA, an effect described principally in the interneuron interneuron synapses, although the mechanism by which the KR produce this effect is yet to be described. CONCLUSIONS: KR act in the hippocampus as modulators of GABA release; they increase or decrease it and hence play a part in maintaining the exquisite balance of neuronal excitability. In abnormal conditions they can also notably upset the balance of this excitability and give rise to firing patterns of an epileptic kind, among other disorders.

Benzodiazepines↗

PubMedDate not supplied

[The role of kainate receptors in the regulation of excitatory synaptic transmission in the hippocampus].

AIMS: To describe the state of the art with regard to the physiology of kainate-like glutamate receptors as modulators in glutamatergic excitatory synaptic transmission in the hippocampus. DEVELOPMENT: Kainate receptors modulate the release of glutamate in the hippocampus in the different synapses that have been studied to date. Their activation can produce a decrease or an increase in glutamate release according to the synapse under study and both types of modulation (increase or decrease) can take place even within the same synaptic connection, depending on the agonist concentration reached by the receptors. Thus, in the synapses that are established among the mossy fibres and the pyramidal neurones in region CA3, high concentrations (> 100 nM) of kainate trigger a drop in glutamate release, whereas low concentrations (< 50 nM) give rise to an increased release of the same neurotransmitter. These actions carried out by the kainate receptors are presynaptic and both ionotropic and metabotropic mechanisms have been proposed to explain them. CONCLUSIONS: Kainate receptors act in the hippocampus as modulators of glutamate release, by either increasing or decreasing it. They therefore help to keep the balance of neuronal excitability, also play a part in neuronal plasticity processes (LTP and LTD) and can trigger, under abnormal conditions, a notable imbalance of this excitability and give rise to epileptic-type firing patterns, among other disorders.

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