Biomedical subjects

Sergi Ferré

Publications and source records attributed to Sergi Ferré.

At least 19 recordsLinked to original sources

PubMed2006

Blockade of adenosine A2A receptors prevents protein phosphorylation in the striatum induced by cortical stimulation.

Previous studies have shown that cortical stimulation selectively activates extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and immediate early gene expression in striatal GABAergic enkephalinergic neurons. In the present study, we demonstrate that blockade of adenosine A2A receptors with caffeine or a selective A2A receptor antagonist counteracts the striatal activation of cAMP-protein kinase A cascade (phosphorylation of the Ser845 residue of the glutamate receptor 1 subunit of the AMPA receptor) and mitogen-activated protein kinase (ERK1/2 phosphorylation) induced by the in vivo stimulation of corticostriatal afferents. The results indicate that A2A receptors strongly modulate the efficacy of glutamatergic synapses on striatal enkephalinergic neurons.

Adenosine A2 Receptor Antagonists↗

PubMed2006

Working memory deficits in transgenic rats overexpressing human adenosine A2A receptors in the brain.

Adenosine receptors in the central nervous system have been implicated in the modulation of different behavioural patterns and cognitive functions although the specific role of A(2A) receptor (A(2A)R) subtype in learning and memory is still unclear. In the present work we establish a novel transgenic rat strain, TGR(NSEhA2A), overexpressing adenosine A(2A)Rs mainly in the cerebral cortex, the hippocampal formation, and the cerebellum. Thereafter, we explore the relevance of this A(2A)Rs overexpression for learning and memory function. Animals were behaviourally assessed in several learning and memory tasks (6-arms radial tunnel maze, T-maze, object recognition, and several Morris water maze paradigms) and other tests for spontaneous motor activity (open field, hexagonal tunnel maze) and anxiety (plus maze) as modification of these behaviours may interfere with the assessment of cognitive function. Neither motor performance and emotional/anxious-like behaviours were altered by overexpression of A(2A)Rs. TGR(NSEhA2A) showed normal hippocampal-dependent learning of spatial reference memory. However, they presented working memory deficits as detected by performance of constant errors in the blind arms of the 6 arm radial tunnel maze, reduced recognition of a novel object and a lack of learning improvement over four trials on the same day which was not observed over consecutive days in a repeated acquisition paradigm in the Morris water maze. Given the interdependence between adenosinic and dopaminergic function, the present results render the novel TGR(NSEhA2A) as a putative animal model for the working memory deficits and cognitive disruptions related to overstimulation of cortical A(2A)Rs or to dopaminergic prefrontal dysfunction as seen in schizophrenic or Parkinson's disease patients.

Analysis of Variance↗

PubMed2006

Heteromeric nicotinic acetylcholine-dopamine autoreceptor complexes modulate striatal dopamine release.

In the striatum, dopamine and acetylcholine (ACh) modulate dopamine release by acting, respectively, on dopamine D(2) autoreceptors and nicotinic ACh (nACh) heteroreceptors localized on dopaminergic nerve terminals. The possibility that functional interactions exist between striatal D(2) autoreceptors and nACh receptors was studied with in vivo microdialysis in freely moving rats. Local perfusion of nicotine in the ventral striatum (shell of the nucleus accumbens) produced a marked increase in the extracellular levels of dopamine, which was completely counteracted by co-perfusion with either the non-alpha(7) nACh receptor antagonist dihydro-beta-erythroidine or the D(2-3) receptor agonist quinpirole. Local perfusion of the D(2-3) receptor antagonist raclopride produced an increase in the extracellular levels of dopamine, which was partially, but significantly, counteracted by coperfusion with dihydro-beta-erythroidine. These findings demonstrate a potent crosstalk between G protein-coupled receptors and ligand-gated ion channels in dopaminergic nerve terminals, with the D(2) autoreceptor modulating the efficacy of non-alpha(7) nACh receptor-mediated modulation of dopamine release. We further demonstrate physical interactions between beta(2) subunits of non-alpha(7) nicotinic acetylcholine receptors and D(2) autoreceptors in co-immunoprecipitation experiments with membrane preparations from co-transfected mammalian cells and rat striatum. These results reveal that striatal non-alpha(7) nicotinic acetylcholine receptors form part of heteromeric dopamine autoreceptor complexes that modulate dopamine release.

Animals↗

PubMed2006

The two-state dimer receptor model: a general model for receptor dimers.

Nonlinear Scatchard plots are often found for agonist binding to G-protein-coupled receptors. Because there is clear evidence of receptor dimerization, these nonlinear Scatchard plots can reflect cooperativity on agonist binding to the two binding sites in the dimer. According to this, the "two-state dimer receptor model" has been recently derived. In this article, the performance of the model has been analyzed in fitting data of agonist binding to A(1) adenosine receptors, which are an example of receptor displaying concave downward Scatchard plots. Analysis of agonist/antagonist competition data for dopamine D(1) receptors using the two-state dimer receptor model has also been performed. Although fitting to the two-state dimer receptor model was similar to the fitting to the "two-independent-site receptor model", the former is simpler, and a discrimination test selects the two-state dimer receptor model as the best. This model was also very robust in fitting data of estrogen binding to the estrogen receptor, for which Scatchard plots are concave upward. On the one hand, the model would predict the already demonstrated existence of estrogen receptor dimers. On the other hand, the model would predict that concave upward Scatchard plots reflect positive cooperativity, which can be neither predicted nor explained by assuming the existence of two different affinity states. In summary, the two-state dimer receptor model is good for fitting data of binding to dimeric receptors displaying either linear, concave upward, or concave downward Scatchard plots.

Adenosine A1 Receptor Agonists↗

PubMed2006

Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers.

The functional role of heteromers of G-protein-coupled receptors is a matter of debate. In the present study, we demonstrate that heteromerization of adenosine A1 receptors (A1Rs) and A2A receptors (A2ARs) allows adenosine to exert a fine-tuning modulation of glutamatergic neurotransmission. By means of coimmunoprecipitation, bioluminescence and time-resolved fluorescence resonance energy transfer techniques, we showed the existence of A1R-A2AR heteromers in the cell surface of cotransfected cells. Immunogold detection and coimmunoprecipitation experiments indicated that A1R and A2AR are colocalized in the same striatal glutamatergic nerve terminals. Radioligand-binding experiments in cotransfected cells and rat striatum showed that a main biochemical characteristic of the A1R-A2AR heteromer is the ability of A2AR activation to reduce the affinity of the A1R for agonists. This provides a switch mechanism by which low and high concentrations of adenosine inhibit and stimulate, respectively, glutamate release. Furthermore, it is also shown that A1R-A2AR heteromers constitute a unique target for caffeine and that chronic caffeine treatment leads to modifications in the function of the A1R-A2AR heteromer that could underlie the strong tolerance to the psychomotor effects of caffeine.

Animals↗

PubMed2006

Stimulation of adenosine receptors selectively activates gene expression in striatal enkephalinergic neurons.

In the striatum, adenosine A2A and dopamine D2 receptors exert reciprocal antagonistic interactions that modulate the function of GABAergic enkephalinergic neurons. We have previously shown that stimulation of adenosine A1 receptors allows the stimulation of A2A receptors to overcome a tonic inhibitory effect of D2 receptors and induce striatal expression of c-fos. In the present work, by studying co-localization of c-Fos immunoreactivity and preproenkephalin and preprodynorphin transcripts, we show that co-administration of the A1 receptor agonist CPA and the A2A receptor agonist CGS 21680 increases the striatal expression of c-fos in GABAergic enkephalinergic but not in GABAergic dynorphinergic neurons. Co-administration of CPA and CGS 21680 also induced a significant increase in the striatal expression of preproenkephalin. The results underscore the role of adenosine in the activation of gene expression in the GABAergic enkephalinergic neuron.

Adenosine↗

PubMed2006

Allosteric modulation of dopamine D2 receptors by homocysteine.

It has been suggested that L-DOPA-induced hyperhomocysteinemia can increase the risk of stroke, heart disease, and dementia and is an additional pathogenetic factor involved in the progression of Parkinson's disease. In Chinese hamster ovary (CHO) cells stably cotransfected with adenosine A(2A) and dopamine D2 receptors, homocysteine selectively decreased the ability of D2 receptor stimulation to internalize adenosine A(2A)-dopamine D2 receptor complexes. Radioligand-binding experiments in the same cell line demonstrated that homocysteine acts as an allosteric D2 receptor antagonist, by selectively reducing the affinity of D2 receptors for agonists but not for antagonists. Mass spectrometric analysis showed that, by means of an arginine (Arg)-thiol electrostatic interaction, homocysteine forms noncovalent complexes with the two Arg-rich epitopes of the third intracellular loop of the D2 receptor, one of them involved in A(2A)-D2 receptor heteromerization. However, homocysteine was unable to prevent or disrupt A(2A)-D2 receptor heteromerization, as demonstrated with Fluorescence Resonance Energy Transfer (FRET) experiments in stably cotransfected HEK cells. The present results could have implications for Parkinson's disease.

Allosteric Regulation↗

PubMed2005

A detailed behavioral analysis of the acute motor effects of caffeine in the rat: involvement of adenosine A1 and A2A receptors.

RATIONALE: There is no consensus on the contribution of adenosine A(1) and A(2A) receptor blockade to motor-activating effects of caffeine. OBJECTIVE: Our aim was to use a detailed and continuous observational method to compare the motor effects induced by caffeine with those induced by selective A(1) and A(2A) receptor antagonists. METHODS: The behavioral repertoire induced by systemic administration of caffeine (3, 10, and 30 mg/kg), A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.2, 4.8 and 7.2 mg/kg), and A(2A) receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3; 1, 3, and 10 mg/kg) was analyzed. The effects of pretreatment with the selective A(1) receptor agonist N (6)-cyclopentyladenosine (CPA; 0.1 mg/g) and the selective A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine (CGS 21680; 0.2 mg/kg) on the pattern of motor activation induced by caffeine, CPT, or MSX-3 were also examined. RESULTS: The pattern of behavioral activation induced by caffeine was better mimicked by CPT than by MSX-3. Coadministration of CPT and MSX-3 gave different results depending on the dose and the type of behavioral response. CPA was more effective at decreasing the activating effects of caffeine and CPT than those of CGS 21680. On the other hand, CGS 21680 was more effective at decreasing the activating effects of MSX-3 than those of caffeine or CPT. Factor analysis revealed a complex three-dimensional behavioral profile for caffeine that was similar to the profile for CPT and was different from the profile for MSX-3. CONCLUSIONS: The results indicate a predominant role for A(1) receptors in the motor-activating effects of acutely administered caffeine.

Adenosine↗

PubMed2005

Involvement of adenosine A1 receptors in the discriminative-stimulus effects of caffeine in rats.

RATIONALE: Caffeine is a non-selective adenosine receptor antagonist in vitro, but involvement of different adenosine receptor subtypes, particularly adenosine A1 and A 2A receptors, in the central effects of caffeine remains a matter of debate. OBJECTIVE: Investigate the role of adenosine A1 and A 2A receptors in the discriminative-stimulus effects of caffeine. METHODS: Rats were trained to discriminate an injection of 30 mg/kg (i.p.) caffeine from saline. The selective A1 receptor antagonist CPT, the selective A 2A receptor antagonist MSX-3 and the non-selective adenosine receptor antagonist DMPX were assessed for their ability to produce caffeine-like discriminative effects. The ability of CPT, MSX-3, the A1 receptor agonist CPA and the A 2A receptor agonist CGS21680 to reduce the discriminative effects of caffeine was also tested. Radioligand binding experiments with membrane preparations from rat striatum and transfected mammalian cell lines were performed to characterize binding affinity profiles of the different adenosine antagonists used in the present study (caffeine, DMPX, CPT and MSX-3) in relation to all known adenosine receptors (A1, A 2A, A 2B, A3). RESULTS: DMPX and CPT, but not MSX-3, produced significant caffeine-like discriminative effects. MSX-3, but not CPT, markedly reduced the discriminative effects of caffeine and the caffeine-like discriminative effects of CPT. Furthermore, the A1 receptor agonist CPA, but not the A 2A agonist CGS21680, reduced caffeine's discriminative effects. CONCLUSIONS: Adenosine A1 receptor blockade is involved in the discriminative-stimulus effects of behaviorally relevant doses of caffeine; A 2A receptor blockade does not play a central role in caffeine's discriminative effects and counteracts the A1 receptor-mediated discriminative-stimulus effects of caffeine.

Adenosine A1 Receptor Antagonists↗

PubMed2005

How receptor mosaics decode transmitter signals. Possible relevance of cooperativity.

It has been demonstrated that receptor-receptor interactions between G-protein-coupled receptors (GPCRs) occur at the plasma-membrane level. It has also been shown that clustering of GPCRs in aggregates or receptor mosaics (RMs) results in the reciprocal modulation of their binding and decoding characteristics. It is hypothesized that cooperativity plays an important part in the decoding of signals processed by RMs of GPCRs. Thus, the binding of the ligand at one receptor alters the likelihood of the same ligand binding at the next site, in the case of RMs, formed by identical receptors and/or by iso-receptors (receptors that bind the same ligand).

Allosteric Regulation↗

PubMed2005

Dimer-based model for heptaspanning membrane receptors.

The existence of intramembrane receptor-receptor interactions for heptaspanning membrane receptors is now fully accepted, but a model considering dimers as the basic unit that binds to two ligand molecules is lacking. Here, we propose a two-state-dimer model in which the ligand-induced conformational changes from one component of the dimer are communicated to the other. Our model predicts cooperativity in binding, which is relevant because the other current models fail to address this phenomenon satisfactorily. Our two-state-dimer model also predicts the variety of responses elicited by full or partial agonists, neutral antagonists and inverse agonists. This model can aid our understanding of the operation of heptaspanning receptors and receptor channels, and, potentially, be important for improving the treatment of cardiovascular, neurological and neuropsychyatric diseases.

Animals↗

PubMed2005

Role of central and peripheral adenosine receptors in the cardiovascular responses to intraperitoneal injections of adenosine A1 and A2A subtype receptor agonists.

1. The cardiovascular effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and the adenosine A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) were investigated in rats implanted with telemetry transmitters for the measurement of blood pressure and heart rate. 2. Intraperitoneal (i.p.) injections of the adenosine A1 receptor agonist CPA led to dose-dependent decreases in both blood pressure and heart rate. These effects of 0.3 mg kg(-1) CPA were antagonized by i.p. injections of the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethyl-xanthine (CPT), but not by i.p. injections of the adenosine A2A receptor antagonist 3-(3-hydroxypropyl)-8-(m-methoxystyryl)-7-methyl-1-propargylxanthine phosphate disodium salt (MSX-3). Injections (i.p.) of the peripherally acting nonselective adenosine antagonist 8-sulfophenyltheophylline (8-SPT) and the purported nonselective adenosine antagonist caffeine also antagonized the cardiovascular effects of CPA. 3. The adenosine A2A agonist CGS 21680 given i.p. produced a dose-dependent decrease in blood pressure and an increase in heart rate. These effects of 0.5 mg kg(-1) CGS 21680 were antagonized by i.p. injections of the adenosine A2A receptor antagonist MSX-3, but not by i.p. injections of the antagonists CPT, 8-SPT or caffeine. 4. Central administration (intracerebral ventricular) of CGS 21680 produced an increase in heart rate, but no change in blood pressure. MSX-3 given i.p. antagonized the effects of the central injection of CGS 21680. 5. These results suggest that adenosine A1 receptor agonists produce decreases in blood pressure and heart rate that are mediated by A1 receptors in the periphery, with little or no contribution of central adenosine A1 receptors to those effects. 6. The heart rate increasing effect of adenosine A2A agonists appears to be mediated by adenosine A2A receptors in the central nervous system. The blood pressure decreasing effect of adenosine A2A agonists is most probably mediated in the periphery.

Adenosine↗

PubMed2005

Molecular mechanisms involved in the adenosine A and A receptor-induced neuronal differentiation in neuroblastoma cells and striatal primary cultures.

Adenosine A1 receptors (A1Rs) and adenosine A(2A) receptors (A(2A)Rs) are the major mediators of the neuromodulatory actions of adenosine in the brain. In the striatum A1Rs and A(2A)Rs are mainly co-localized in the GABAergic striatopallidal neurons. In this paper we show that agonist-induced stimulation of A1Rs and A(2A)Rs induces neurite outgrowth processes in the human neuroblastoma cell line SH-SY5Y and also in primary cultures of striatal neuronal precursor cells. The kinetics of adenosine-mediated neuritogenesis was faster than that triggered by retinoic acid. The triggering of the expression of TrkB neurotrophin receptor and the increase of cell number in the G1 phase by the activation of adenosine receptors suggest that adenosine may participate in early steps of neuronal differentiation. Furthermore, protein kinase C (PKC) and extracellular regulated kinase-1/2 (ERK-1/2) are involved in the A1R- and A(2A)R-mediated effects. Inhibition of protein kinase A (PKA) activity results in a total inhibition of neurite outgrowth induced by A(2A)R agonists but not by A1R agonists. PKA activation is therefore necessary for A(2A)R-mediated neuritogenesis. Co-stimulation does not lead to synergistic effects thus indicating that the neuritogenic effects of adenosine are mediated by either A1 or A(2A) receptors depending upon the concentration of the nucleoside. These results are relevant to understand the mechanisms by which adenosine receptors modulate neuronal differentiation and open new perspectives for considering the use of adenosine agonists as therapeutic agents in diseases requiring neuronal repair.

Adenosine↗

PubMed2005

Role of adenosine in the control of homosynaptic plasticity in striatal excitatory synapses.

Long-lasting, activity-dependent changes in synaptic efficacy at excitatory synapses are critical for experience-dependent synaptic plasticity. Synaptic plasticity at excitatory synapses is determined both presynaptically by changes in the probability of neurotransmitter release, and postsynaptically by changes in the availability of functional postsynaptic glutamate receptors. Two kinds of synaptic plasticity have been described. In homosynaptic or Hebbian plasticity, the events responsible for synaptic strengthening occur at the same synapse as is being strengthened. Homosynaptic plasticity is activity-dependent and associative, because it associates the firing of a postsynaptic neuron with that of the presynaptic neuron. Heterosynaptic plasticity, on the other hand, is activity-independent and the synaptic strength is modified as a result of the firing of a third, modulatory neuron. It has been suggested that long-term changes in synaptic strength, which are associated with gene transcription, can only be induced with the involvement of heterosynaptic plasticity. The neuromodulator adenosine plays an elaborated pre- and postsynaptic control of glutamatergic neurotransmission. This paper reviews the evidence suggesting that in some striatal excitatory synapses, adenosine can provide the heterosynaptic-like modulation essential for stabilizing homosynaptic plasticity without the need of a "third, modulatory neuron".

Adenosine↗

PubMed2005

Role of electrostatic interaction in receptor-receptor heteromerization.

Using pull-down and mass spectrometry experiments, we have previously demonstrated that adenosine A2A-dopamine D2 receptor-receptor heteromerization depends on an electrostatic interaction between an Arg-rich epitope from the third intracellular loop of the D2 receptor (217RRRRKR222) and two adjacent Asp residues (DD401-402) or a phosphorylated Ser (pS374) residue in the carboxyl terminus of the A2A receptor. It has been demonstrated recently that a specific region in the carboxyl terminus of the dopamine D1 receptor (L387-L416) and a specific region in the carboxyl terminus of the NR1-1 subunit of the NMDA receptor (E834-S938) are involved in D1-NMDA receptor-receptor heteromerization. Careful perusal of these interacting regions shows the presence of a phosphorylated serine (pS397) and adjacent glutamates (EE404-405) in the D1 receptor, whereas NR1-1 contains three adjacent Arg residues (RRR893-896). These epitopes are highly conserved in all species, a sign that the epitopes are likely to be involved in a physiologically significant activity. If similar epitopes are found to be involved in the formation of receptor heteromers other than A2A-D2 and D1-NMDA, the epitope-epitope electrostatic interaction might represent an important general mechanism underlying receptor- receptor interactions.

Amino Acid Sequence↗

PubMed2005

How proteins come together in the plasma membrane and function in macromolecular assemblies: focus on receptor mosaics.

Some theoretical aspects on structure and function of proteins have been discussed previously. Proteins form multimeric complexes, as they have the capability of binding other proteins (Lego property) resulting in multimeric complexes capable of emergent functions. Multimeric proteins might have either a genomic or a postgenomic origin. Proteins spanning the plasma membrane have been analyzed by considering the effects of the microenvironment in which the protein is embedded. In particular, the different effects of the hydrophilic (extracellular and intracellular) versus the lipophilic (intramembrane) environment have been considered. These aspects have been discussed in the framework of membrane microdomains, in particular, the so-called rafts. In alpha-helix proteins the individual peptide dipoles align to produce a macrodipole crossing the entire membrane. This macrodipole has its positive (extracellular) pole at the N-terminal end of the helix and its negative (intracellular) pole at the C-terminal end. This arrangement has been analyzed in the framework of the counter-ion atmosphere, that is, the formation of a cloud of small ions bearing an opposite charge. Excitable cells reverse their resting potential during the all-or-none action potentials. Hence, the extracellular side of the plasma membrane becomes negative with respect to the intracellular side. This change of polarization affects also the direction and magnitude of the alpha-helix dipole in view of the fact that there is a displacement of the counter ions. The oscillation in the intensity of the dipole caused by the action potentials opens the possibility of an interaction among dipoles by electromagnetic waves.

Animals↗

PubMed2005

Computer-assisted image analysis of caveolin-1 involvement in the internalization process of adenosine A2A-dopamine D2 receptor heterodimers.

A functional aspect of horizontal molecular networks has been investigated experimentally, namely the heteromerization between adenosine A2A and dopamine D2 receptors and the possible role of caveolin-1 in the co-trafficking of these molecular complexes. This study has been carried out by means of computer-assisted image analysis procedure of laser images of membrane immunoreactivity of caveolin-1, A2A, D1, and D2 receptors obtained in two clones of Chinese hamster ovary cells one transfected with A2A and dopamine D1 receptors and the other one with A2A and D2 receptors. Cells were treated for 3 h with 10 microM D1 receptor agonist SKF 38393, 50 microM D2-D3 receptor agonist quinpirole, and 200 nM A2A receptor agonist CGS 21680. In A2A-D1-cotransfected cells, caveolin-1 was found to colocalize with both A2A and D1 receptors and treatment with SKF 38393 induced internalization of caveolin-1 and D1 receptors, with a preferential internalization of D1 receptors colocalized with caveolin-1. In A2A-D2-cotransfected cells, caveolin-1 was found to colocalize with both A2A and D2 receptors and either CGS 21680 or quinpirole treatment induced internalization of caveolin-1 and A2A and D2 receptors, with a preferential internalization of A2A and D2 receptors colocalized with caveolin-1. The results suggest that A2A and D2 receptors and caveolin-1 likely interact forming a macrocomplex that internalizes upon agonist treatment. These observations are discussed in the frame of receptor oligomerization and of the possible functional role of caveolin-1 in the process of co-internalization and, hence, in controlling the permanence of receptors at the plasma membrane level (prerequisite for receptor mosaic organization and plastic adjustments) and in the control of receptor desensitization.

Animals↗

PubMed2005

Receptor-receptor interactions, receptor mosaics, and basic principles of molecular network organization: possible implications for drug development.

The phenomenon of receptor-receptor interactions was hypothesized by Agnati and Fuxe in the 1980s, and several indirect proofs were provided in the following years by means of in vitro binding experiments and in vivo experiments in physiological and pathological animal models. This paper aims to outline some of the most important features and consequences of this phenomenon in the frame of the structural and functional aspects of molecular networks. In particular, the concepts of receptor mosaic (RM), and of horizontal and vertical molecular networks (HMNs, VMNs, respectively) are illustrated. To discuss some aspects of the functional organization of molecular networks, not only new data on protein-protein interactions but also the biochemical mechanism of cooperativity will be used. On this basis, some theoretical deductions can be drawn that allow a tentative classification of the RMs and the proposal of the extension of the concept of branching point introduced for enzymes to the possible switching role of some RMs in directing signals to various VMNs. Finally, the cooperativity phenomenon and the so-called symmetry rule will be used to introduce a proper mathematical approach that characterizes RMs as to their receptor composition, receptor topography, and order of receptor activation inside the RM. These new data on G protein-coupled receptors and molecular network organization indicate possible new approaches for drug development.

Animals↗