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S Ferré

Publications and source records attributed to S Ferré.

At least 19 recordsLinked to original sources
PubMed2006

Intramembrane receptor-receptor interactions: a novel principle in molecular medicine.

In 1980/81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor-receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor-receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor-receptor interactions namely the presence of regulated cooperativity via receptor-receptor interactions in receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor-receptor interactions are outlined and long-lived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval processes. Intramembrane receptor-receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson's disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 agonists) and depression (galanin receptor antagonists). The A2A/D2, A2A/D3 and A2A/mGluR5 heteromers and heteromeric complexes with their possible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A/D4 heteromers. Finally, the impact of intramembrane receptor-receptor interactions in molecular medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.

Animals↗
PubMed2006

Receptor-receptor interactions involving adenosine A1 or dopamine D1 receptors and accessory proteins.

The molecular basis for the known intramembrane receptor-receptor interactions among heptahelical receptors (G protein coupled receptors, GPCR) was postulated to be heteromerization based on receptor subtype specific interactions between different types of homomers of GPCR. Adenosine and dopamine receptors in the basal ganglia have been fundamental to demonstrate the existence of receptor heteromers and the functional consequences of such molecular interactions. The heterodimer is only one type of heteromeric complex and the evidence is equally compatible with the existence of higher order heteromeric complexes, where also adapter proteins such as homer proteins and scaffolding proteins can exist, assisting in the process of linking the GPCR and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular basis for learning and memory. Heteromerization of D(2) dopamine and A(2A) adenosine receptors is reviewed by Fuxe in another article in this special issue. Here, heteromerization between D(1) dopamine and A(1) adenosine receptors is reviewed. Heteromers formed by dopamine D(1) and D(2) receptors and by adenosine A(1) and A(2A) receptors also occur in striatal cells and open new perspectives to understand why two receptors with apparently opposite effects are expressed in the same neuron and in the nerve terminals. The role of accessory proteins also capable of interacting with receptor-receptor heteromers in regulating the traffic and the molecular physiology of these receptors is also discussed. Overall, the knowledge of the reason why such complex networks of receptor-receptor and receptor-protein interactions occur in striatal cells is crucial to develop new strategies to combat neurological and neuropsychiatric diseases.

Animals↗
PubMed2006

Heterodimeric adenosine receptors: a device to regulate neurotransmitter release.

Since 1990 it has been known that dimers are the basic functional form of nearly all G-protein-coupled receptors (GPCRs) and that homo- and heterodimerization may play a key role in correct receptor maturation and trafficking to the plasma membrane. Nevertheless, homo- and heterodimerization of GPCR has become a matter of debate especially in the search for the precise physiological meaning of this phenomenon. This article focuses on how heterodimerization of adenosine A1 and A2A receptors, which are coupled to apparently opposite signalling pathways, allows adenosine to exert a fine-tuning modulation of striatal glutamatergic neurotransmission, providing a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release.

Adenosine↗
PubMed2004

Energy gradients for the homeostatic control of brain ECF composition and for VT signal migration: introduction of the tide hypothesis.

The present paper enlightens a new point of view on brain homeostasis and communication, namely how the brain takes advantage of different chemical-physical phenomena such as pressure waves, and temperature and concentration gradients to allow the renewal of the extra-cellular fluid (i.e., the homeostasis of the brain internal milieu) as well as some forms of intercellular communications (Volume Transmission) at an energy cost much lower than the classical synaptic transmission (the prototype of Wiring Transmission). In particular, the possible functional meaning of the intracranial pressure waves is discussed in the frame of the so called "tide hypothesis" which maintains that the pressure waves, created by the cardiac pump, modulate the cerebro-spinal fluid flow from and towards the subarachnoid space as well as towards and from the Virchow-Robin spaces. These fluid push-pull movements favor both the migration of signals and the extra-cellular fluid renewal, especially in the cerebral cortex.

Animals↗
PubMed2004

Studies on homocysteine plasma levels in Alzheimer's patients. Relevance for neurodegeneration.

Homocysteine (HC) may work inter alia as a Volume Transmission signal since HC is present in the brain and cerebrospinal fluid and binds to NMDA receptors. Furthermore, in cell cultures increased HC formation increases its export. In the present study we have shown that after intravenous injection in intact animals HC penetrates the blood-brain barrier. Hence, it works as a blood-born humoral signal. Furthermore, we have studied HC plasma levels in a group of Alzheimer's (AD) patients and compared with a group of age-matched patients. It has been confirmed that a positive correlation exists between age and HC plasma levels in the control group, but not in the AD patients. These results may depend on the fact that in AD patients high HC plasma levels (possibly associated with high glycine levels and/or excessive glutamate release) have favored neurodegeneration and, once this pathological process has been triggered off, the plasma HC levels become independent of the "physiological" aging-induced increase of HC plasma levels.

Aged↗
PubMed2004

Striatal plasticity at the network level. Focus on adenosine A2A and D2 interactions in models of Parkinson's Disease.

Behavioral and microdialysis studies have been performed on antagonistic A(2A)/D(2) interactions in animal models of Parkinson's Disease. The behavioral analysis involved studies on locomotor activity in reserpinized mice, haloperidol-induced catalepsy in rats and rotational behavior in rats with unilateral 6-OHDA lesions of the ascending DA pathways (Ungerstedt model). Dual probe microdialysis studies were indirectly performed on the striatopallidal GABA neurons by studying extracellular glutamate levels in the striatum and globus pallidus of the awake freely moving rat. The striatum was perfused with A(2A) and/or D(2) agonists via reverse microdialysis. The results show that the A(2A) antagonists SCH58261 and KF17837 can increase locomotor activity in reserpinized mice and produce contralateral rotational behavior only after administration of subthreshold doses of l-DOPA or the D(2) like agonist quinpirole. Furthermore, antagonizing the A(2A) receptor (R) reduced haloperidol induced catalepsy. The behavioral results underline the view that A(2A) antagonists act by blocking A(2A) R in A(2A)/D(2) heterodimers where A(2A) R inhibits the D(2) R transduction and D(2) inhibits the adenylate cyclase (AC) activated by A(2A) R. The microdialysis studies show that the A(2A) agonist CGS21680 striatally coperfused with the D(2) agonist quinpirole more potently counteract the D(2) agonist (quinpirole) induced reduction of pallidal glutamate levels in the DA denervated vs the control striatum indicating an enhancement of the inhibitory A(2A)/D(2) interaction. In the DA denervated but not in the control striatum the A(2A) agonist CGS21680 could strongly increase striatal glutamate levels, indicating an increased receptor signaling in the A(2A) R located on the striatal glutamate terminals, where also D(2) like R exist, here probably as D(4). Thus, the signaling of this A(2A) R may be set free by the loss of D(4) tone on the AC activated by A(2A) in this postulated A(2A)/D(4) heteromer on the glutamate terminals. Taken together, the results indicate that the antiparkinsonian actions of A(2A) antagonists probably are produced by blockade of A(2A) R in the A(2A)/D(2) heterodimers mainly located in the striatopallidal GABA neurons.

Adenosine A2 Receptor Antagonists↗
PubMed2003

Receptor heteromerization in adenosine A2A receptor signaling: relevance for striatal function and Parkinson's disease.

Recently evidence has been presented that adenosine A2A and dopamine D2 receptors form functional heteromeric receptor complexes as demonstrated in human neuroblastoma cells and mouse fibroblast Ltk- cells. These A2A/D2 heteromeric receptor complexes undergo coaggregation, cointernalization, and codesensitization on D2 or A2A receptor agonist treatments and especially after combined agonist treatment. It is hypothesized that the A2A/D2 receptor heteromer represents the molecular basis for the antagonistic A2A/D2 receptor interactions demonstrated at the biochemical and behavioral levels. Functional heteromeric complexes between A2A and metabotropic glutamate 5 receptors (mGluR5) have also recently been demonstrated in HEK-293 cells and rat striatal membrane preparations. The A2A/mGluR5 receptor heteromer may account for the synergism found after combined agonist treatments demonstrated in different in vitro and in vivo models. D2, A2A, and mGluR5 receptors are found together in the dendritic spines of the striatopallidal GABA neurons. Therefore, possible D2/A2A/mGluR5 multimeric receptor complexes and the receptor interactions within them may have a major role in controlling the dorsal and ventral striatopallidal GABA neurons involved in Parkinson's disease and in schizophrenia and drug addiction, respectively.

Animals↗
PubMed2003

Possible role of intramembrane receptor-receptor interactions in memory and learning via formation of long-lived heteromeric complexes: focus on motor learning in the basal ganglia.

Learning in neuronal networks occurs by instructions to the neurons to change their synaptic weights (i.e., efficacies). According to the present model a molecular mechanism that can contribute to change synaptic weights may be represented by multiple interactions between membrane receptors forming aggregates (receptor mosaics) via oligomerization at both pre- and post-synaptic level. These assemblies of receptors together with inter alia single receptors, adapter proteins, G-proteins and ion channels form the membrane bound part of a complex three-dimensional (3D) molecular circuit, the cytoplasmic part of which consists especially of protein kinases, protein phosphatases and phosphoproteins. It is suggested that this molecular circuit has the capability to learn and store information. Thus, engram formation will depend on the resetting of 3D molecular circuits via the formation of new receptor mosaics capable of addressing the transduction of the chemical messages impinging on the cell membrane to certain sets of G-proteins. Short-term memory occurs by a transient stabilization of the receptor mosaics producing the appropriate change in the synaptic weight. Engram consolidation (long-term memory) may involve intracellular signals that translocate to the nucleus to cause the activation of immediate early genes and subsequent formation of postulated adapter proteins which stabilize the receptor mosaics with the formation of long-lived heteromeric receptor complexes. The receptor mosaic hypothesis of the engram formation has been formulated in agreement with the Hebbian rule and gives a novel molecular basis for it by postulating that the pre-synaptic activity change in transmitter and modulator release reorganizes the receptor mosaics at post-synaptic level and subsequently at pre-synaptic level with the formation of novel 3D molecular circuits leading to a different integration of chemical signals impinging on pre- and post-synaptic membranes hence leading to a new value of the synaptic weight. Engram retrieval is brought about by the scanning of the target networks by the highly divergent arousal systems. Hence, a continuous reverberating process occurs both at the level of the neural networks as well as at the level of the 3D molecular circuits within each neuron of the network until the appropriate tuning of the synaptic weights is obtained and, subsequently, the reappearance of the engram occurs. Learning and memory in the basal ganglia is discussed in the frame of the present hypothesis. It is proposed that formation of long-term memories (consolidated receptor mosaics) in the plasma membranes of the striosomal GABA neurons may play a major role in the motivational learning of motor skills of relevance for survival. In conclusion, long-lived heteromeric receptor complexes of high order may be crucial for learning, memory and retrieval processes, where extensive reciprocal feedback loops give rise to coherent synchronized neural activity (binding) essential for a sophisticated information handling by the central nervous system.

Animals↗
PubMed2002

Interactions among adenosine deaminase, adenosine A(1) receptors and dopamine D(1) receptors in stably cotransfected fibroblast cells and neurons.

The role of adenosine deaminase in the interactions between adenosine A(1) and dopamine D(1) receptors was studied in a mouse fibroblast cell line stably cotransfected with human D(1) receptor and A(1) receptor cDNAs (A(1)D(1) cells). Confocal laser microscopy analysis showed a high degree of adenosine deaminase immunoreactivity on the membrane of the A(1)D(1) cells but not of the D(1) cells (only cotransfected with human D(1) receptor cDNAs). In double immunolabelling experiments in A(1)D(1) cells and cortical neurons a marked overlap in the distribution of the A(1) receptor and adenosine deaminase immunoreactivities and of the D(1) receptor and adenosine deaminase immunoreactivities was found. Quantitative analysis of A(1)D(1) cells showed that adenosine deaminase immunoreactivity to a large extent colocalizes with A(1) and D(1) receptor immunoreactivity, respectively. The A(1) receptor agonist caused in A(1)D(1) cells and in cortical neurons coaggregation of A(1) receptors and adenosine deaminase, and of D(1) receptors and adenosine deaminase. The A(1) receptor agonist-induced aggregation was blocked by R-deoxycoformycin, an irreversible adenosine deaminase inhibitor. The competitive binding experiments with the D(1) receptor antagonist [(3)H]SCH-23390 showed that the D(1) receptors had a better fit for two binding sites for dopamine, and treatment with the A(1) receptor agonist produced a disappearance of the high-affinity site for dopamine at the D(1) receptor. R-Deoxycoformycin treatment, which has previously been shown to block the interaction between adenosine deaminase and A(1) receptors, and which is crucial for the high-affinity state of the A(1) receptor, also blocked the A(1) receptor agonist-induced loss of high-affinity D(1) receptor binding. The conclusion of the present studies is that the high-affinity state of the A(1) receptor is essential for the A(1) receptor-mediated antagonistic modulation of D(1) receptors and for the A(1) receptor-induced coaggregates of A(1) and adenosine deaminase, and of D(1) and adenosine deaminase. Thus, the confocal experiments indicate that both A(1) and D(1) receptors form agonist-regulated clusters with adenosine deaminase, where the presence of a structurally intact adenosine deaminase bound to A(1) receptors is important for the A(1)-D(1) receptor-receptor interaction at the level of the D(1) receptor recognition.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

Adenosine A2A agonist CGS 21680 decreases the affinity of dopamine D2 receptors for dopamine in human striatum.

Adenosine A2A receptors (A2AR) and dopamine D2 receptors (D2R) are highly concentrated in the striatum, where they are co-localized and exert reciprocal antagonistic interactions. It has been suggested that the A2R/D2R interactions might provide a therapeutic approach for basal ganglia disorders, such as Parkinson's disease, and schizophrenia. In the present work evidence is presented for the existence of an A2AR/D2R interaction in human brain by using quantitative autoradi- ography. The areas analyzed were the dorsal caudate nucleus and putamen. Parallel studies were performed in rat striatal sections. The A2AR agonist CGS 21680 was found to significantly increase IC50 values of competitive inhibition curves of the D2R/D3R antagonist [125I]iodosulpiride vs dopamine both in rat striatal and human striatal brain sections.

Adenosine↗
PubMed2001

The selective mGlu(5) receptor agonist CHPG inhibits quinpirole-induced turning in 6-hydroxydopamine-lesioned rats and modulates the binding characteristics of dopamine D(2) receptors in the rat striatum: interactions with adenosine A(2a) receptors.

In 6-hydroxydopamine-lesioned rats, the selective mGlu(5) receptor agonist (RS)-2-Cholro-5-Hydroxyphenylglycine (CHPG, 1-6 microg/10 microl intracerebroventricularly) significantly inhibited contralateral turning induced by quinpirole and, to a lesser extent, that induced by SKF 38393. The inhibitory effects of CHPG on quinpirole-induced turning were significantly potentiated by an adenosine A(2A) receptor agonist (CGS 21680, 0.2 mg/kg IP) and attenuated by an A(2A) receptor antagonist (SCH 58261, 1 mg/kg IP). In rat striatal membranes, CHPG (100-1,000 nM) significantly reduced the affinity of the high-affinity state of D(2) receptors for the agonist, an effect potentiated by CGS 21680 (30 nM). These results show the occurrence of functional interactions among mGlu(5), adenosine A(2A), and dopamine D(2) receptors in the regulation of striatal functioning, and suggest that mGlu(5) receptors may be regarded as alternative/integrative targets for the development of therapeutic strategies in the treatment of Parkinson's disease.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

Adenosine/dopamine interaction: implications for the treatment of Parkinson's disease.

Evidence for a role of dopaminergic neurotransmission in the motor effects of adenosine antagonists, such as caffeine, is reviewed, based on the existence of specific antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the striatum. Both adenosine A(1) and adenosine A(2A) receptor antagonists induce motor activation in rodents. At least a certain degree of dopaminergic activity is required to obtain adenosine antagonist-induced motor activation, with adenosine A(1) antagonists being the most sensitive and non-selective adenosine antagonists the most resistant to striatal dopamine depletion. When considering long-term treatment with adenosine antagonists concomitant administration of dopamine agonists might be required in order to obtain strong motor effects (cross-sensitization) and to avoid the development of telerance.

Journal Article↗
PubMed2000

Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes.

The possible molecular basis for the previously described antagonistic interactions between adenosine A(1) receptors (A(1)R) and dopamine D(1) receptors (D(1)R) in the brain have been studied in mouse fibroblast Ltk(-) cells cotransfected with human A(1)R and D(1)R cDNAs or with human A(1)R and dopamine D(2) receptor (long-form) (D(2)R) cDNAs and in cortical neurons in culture. A(1)R and D(1)R, but not A(1)R and D(2)R, were found to coimmunoprecipitate in cotransfected fibroblasts. This selective A(1)R/D(1)R heteromerization disappeared after pretreatment with the D(1)R agonist, but not after combined pretreatment with D(1)R and A(1)R agonists. A high degree of A(1)R and D(1)R colocalization, demonstrated in double immunofluorescence experiments with confocal laser microscopy, was found in both cotransfected fibroblast cells and cortical neurons in culture. On the other hand, a low degree of A(1)R and D(2)R colocalization was observed in cotransfected fibroblasts. Pretreatment with the A(1)R agonist caused coclustering (coaggregation) of A(1)R and D(1)R, which was blocked by combined pretreatment with the D(1)R and A(1)R agonists in both fibroblast cells and in cortical neurons in culture. Combined pretreatment with D(1)R and A(1)R agonists, but not with either one alone, substantially reduced the D(1)R agonist-induced accumulation of cAMP. The A(1)R/D(1)R heteromerization may be one molecular basis for the demonstrated antagonistic modulation of A(1)R of D(1)R receptor signaling in the brain. The persistence of A(1)R/D(1)R heteromerization seems to be essential for the blockade of A(1)R agonist-induced A(1)R/D(1)R coclustering and for the desensitization of the D(1)R agonist-induced cAMP accumulation seen on combined pretreatment with D(1)R and A(1)R agonists, which indicates a potential role of A(1)R/D(1)R heteromers also in desensitization mechanisms and receptor trafficking.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2000

Modulation of [(35)S]GTPgammaS binding to chinese hamster ovary cell membranes by D(2(short)) dopamine receptors.

Rat dopamine D(2short) expressed in Chinese hamster ovary (CHO) cells were characterized by means of activation of [(35)S]-guanosine 5'-O-(gamma-thiotriphosphate) ([(35)S]GTPgammaS) binding and inhibition of [(3)H]raclopride binding. Among 18 dopaminergic ligands studied dopamine, NPA, apomorphine and quinpirole were full agonists in activation of [(35)S]GTPgammaS binding, while seven ligands were partial agonists with efficacies from 16 to 69% of the effect of dopamine and seven ligands were antagonists having no effect on the basal level of [(35)S]GTPgammaS binding, but inhibited dopamine-dependent activation in a dose-response manner. Despite the different efficacies, the potencies of all 18 ligands to modulate [(35)S]GTPgammaS binding revealed a good correlation with their potencies to inhibit [(3)H]raclopride binding in the CHO cell membranes. This indicates that the binding of the ligand to the receptor determines its potency, but has no direct correlation with its intrinsic activity.

Animals↗
PubMed2000

Evidence for adenosine/dopamine receptor interactions: indications for heteromerization.

Evidence has been obtained for adenosine/dopamine interactions in the central nervous system. There exists an anatomical basis for the existence of functional interactions between adenosine A(1)R and dopamine D(1)R and between adenosine A(2A) and dopamine D(2) receptors in the same neurons. Selective A(1)R agonists affect negatively the high affinity binding of D(1) receptors. Activation of A(2A) receptors leads to a decrease in receptor affinity for dopamine agonists acting on D(2) receptors, specially of the high-affinity state. These interactions have been reproduced in cell lines and found to be of functional significance. Adenosine/dopamine interactions at the behavioral level probably reflect those found at the level of dopamine receptor binding and transduction. All these findings suggest receptor subtype-specific interactions between adenosine and dopamine receptors that may be achieved by molecular interactions (e.g., receptor heterodimerization). At the molecular level adenosine receptors can serve as a model for homomeric and heteromeric protein-protein interactions. A1R forms homodimers in membranes and also form high-order molecular structures containing also heterotrimeric G-proteins and adenosine deaminase. The occurrence of clustering also clearly suggests that G-protein- coupled receptors form high-order molecular structures, in which multimers of the receptors and probably other interacting proteins form functional complexes. In view of the occurrence of homodimers of adenosine and of dopamine receptors it is speculated that heterodimers between these receptors belonging to two different families of G-protein-coupled receptors can be formed. Evidence that A1/D1 can form heterodimers in cotransfected cells and in primary cultures of neurons has in fact been obtained. In the central nervous system direct and indirect receptor-receptor interactions via adaptor proteins participate in neurotransmission and neuromodulation and, for example, in the establishment of high neural functions such as learning and memory.

Animals↗
PubMed2000

Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A2A receptors in dopamine D2 receptor regulation in the rat dopamine-denervated striatum.

It has been shown that striatal adenosine A2A receptors can antagonistically interact with dopamine D2 receptors at the membrane level leading to a decrease in the affinity and efficacy of D2 receptors. Extracellular recordings and rotational behaviour were employed to obtain a correlate to these findings in an animal model of Parkinson's disease (PD). The recordings were performed in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced catecholamine depletion. While recording in the dopamine-depleted striatum, local applications of the dopamine D2 agonist quinpirole reduced neuronal activity. However, when the adenosine A2A antagonist MSX-3 was applied simultaneously with quinpirole, the inhibition of neuronal firing seen after quinpirole alone was significantly potentiated (P< 0.001, n = 11). In contrast, local application of CGS 21680 attenuated the effect of quinpirole. The doses of MSX-3 and CGS 21680 used to achieve the modulation of quinpirole action had no effect per se on striatal neuronal firing. Furthermore, rotational behaviour revealed that MSX-3 dose-dependently increased the number of turns when administrated together with a threshold dose of quinpirole while no enhancement was achieved when MSX-3 was combined with SKF 38393. MSX-3 alone did not induce rotational behaviour. In conclusion, this study shows that low ineffective doses of MSX-3 enhance the effect of quinpirole on striatal firing rate, while the A2A agonist exerts the opposite action. This mechanism gives a therapeutic potential to A2A antagonists in the treatment of PD by enhancing D2 receptor function.

Adenosine↗