Enhanced dopamine D2 receptor function in hypothalamus and corpus striatum: their role in liver, plasma and in vitro hepatocyte ALDH regulation in ethahol treated rats

Dopamine D2 receptors are involved in ethanol self- administration behavior and also suggested to mediate the onset and offset of ethanol drinking. In the present study, we investigated dopamine (DA) content and Dopamine D2 (DA D2) receptors in the hypothalamus and corpus striatum of ethanol treated rats and aldehyde dehydrogenase (ALDH) activity in the liver and plasma of ethanol treated rats and in vitro hepatocyte cultures. Hypothalamic and corpus striatal DA content decreased significantly (P\0.05, P\0.001 respectively) and homovanillic acid/ dopamine (HVA/DA) ratio increased significantly (P\0.001) in ethanol treated rats when compared to control. Scatchard analysis of [3H] YM-09151-2 binding to DA D2 receptors in hypothalamus showed a significant increase (P\0.001) in Bmax without any change in Kd in ethanol treated rats compared to control. The Kd of DA D2 receptors significantly decreased (P\0.05) in the corpus striatum of ethanol treated rats when compared to control. DA D2 receptor affinity in the hypothalamus and corpus striatum of control and ethanol treated rats fitted to a single site model with unity as Hill slope value. The in vitro studies on hepatocyte cultures showed that 10-5 M and 10-7 M DA can reverse the increased ALDH activity in 10% ethanol treated cells to near control level. Sulpiride, an antagonist of DA D2, reversed the effect of dopamine on 10% ethanol induced ALDH activity in hepatocytes. Our results showed a decreased dopamine concentration with enhanced DA D2 receptors in the hypothalamus and corpus striatum of ethanol treated rats. Also, increased ALDH was observed in the plasma and liver of ethanol treated rats and in vitro hepatocyte cultures with 10% ethanol as a compensatory mechanism for increased aldehyde production due to increased dopamine metabolism. A decrease in dopamine concentration in major brain regions is coupled with an increase in ALDH activity in liver and plasma, which contributes to the tendency for alcoholism. Since the administration of 10-5 M and 10-7 M DA can reverse the increased ALDH activity in ethanol treated cells to near control level, this has therapeutic application to correct ethanol addicts from addiction due to allergic reaction observed in aldehyde accumulation.

Down-regulation of cerebellar 5-HT2C receptors in pilocarpine-induced epilepsy in rats: Therapeutic role of Bacopa monnieri extract

Epilepsy is a syndrome of episodic brain dysfunction characterized by recurrent unpredictable, spontaneous seizures. Cerebellar dysfunction is a recognized complication of temporal lobe epilepsy and it is associated with seizure generation, motor deficits and memory impairment. Serotonin is known to exert a modulatory action on cerebellar function through 5HT2C receptors. 5-HT2C receptors are novel targets for developing anticonvulsant drugs. In the present study, we investigated the changes in the 5-HT2C receptors binding and gene expression in the cerebellum of control, epileptic and Bacopa monnieri treated epileptic rats. There was a significant down regulation of the 5-HT content (pb0.001), 5-HT2C gene expression (pb0.001) and 5-HT2C receptor binding (pb0.001) with an increased affinity (pb0.001). Carbamazepine and B. monnieri treatments to epileptic rats reversed the down regulated 5-HT content (pb0.01), 5-HT2C receptor binding (pb0.001) and gene expression (pb0.01) to near control level. Also, the Rotarod test confirms the motor dysfunction and recovery by B. monnieri treatment. These data suggest the neuroprotective role of B. monnieri through the upregulation of 5-HT2C receptor in epileptic rats. This has clinical significance in the management of epilepsy

5-HT2C and NMDA Receptors, IP3, cGMP and cAMP Functional Regulation in Pilocarpine Induced Temporal Lobe Epilepsy in Rats: Neuroprotective Role of Bacopa monnieri

Department of Biotechnology, Cochin University of Science and Technology

GABAA and GABAB Receptor Gene Expression and Functional Regulation During Pancreatic Regeneration and Insulin Secretion in Rats

The present study demonstrate the functional alterations of the GABAA and GABAB receptors and the gene expression during the regeneration of pancreas following partial pancreatectomy. The role of these receptors in insulin secretion and pancreatic DNA synthesis using the specific agonists and antagonists also are studied in vitro. The alterations of GABAA and GABAR receptor function and gene expression in the brain stem, crebellum and hypothalamus play an important role in the sympathetic regulation of insulin secretion during pancreatic regeneration. Previous studies have given much information linking functional interaction between GABA and the peripheral nervous system. The involvement of specific receptor subtypes functional regulation during pancreatic regeneration has not given emphasis and research in this area seems to be scarce. We have observed a decreased GABA content, down regulation of GABAA receptors and an up regulation of GABAB receptors in the cerebral cortex, brain stem and hypothalamus. Real Time-PCR analysis confirmed the receptor data in the brain regions. These alterations in the GABAA and GABAB receptors of the brain are suggested to govern the regenerative response and growth regulation of the pancreas through sympathetic innervation. In addition, receptor binding studies and Real Time-PCR analysis revealed that during pancreatic regeneration GABAA receptors were down regulated and GABAB receptors were up regulated in pancreatic islets. This suggests an inhibitory role for GABAA receptors in islet cell proliferation i.e., the down regulation of this receptor facilitates proliferation. Insulin secretion study during 1 hour showed GABA has inhibited the insulin secretion in a dose dependent manner in normal and hyperglycaemic conditions. Bicuculline did not antagonize this effect. GABAA agonist, muscimol inhibited glucose stimulated insulin secretion from pancreatic islets except in the lowest concentration of 1O-9M in presence of 4mM glucose.Musclmol enhanced insulin secretion at 10-7 and 10-4M muscimol in presence of 20mM glucose- 4mM glucose represents normal and 20mM represent hyperglycaemic conditions. GABAB agonist, baclofen also inhibited glucose induced insulin secretion and enhanced at the concentration of 1O-5M at 4mM glucose and at 10-9M baclofen in presence of 20mM glucose. This shows a differential control of the GABAA and GABAB receptors over insulin release from the pancreatic islets. During 24 hours in vitro insulin secretion study it showed that low concentration of GABA has inhibited glucose stimulated insulin secretion from pancreatic islets. Muscimol, the GABAA agonist, inhibited the insulin secretion but, gave an enhanced secretion of insulin in presence of 4mM glucose at 10-7 , 10-5 and 1O-4M muscimol. But in presence of 20mM glucose muscimol significantly inhibited the insulin secretion. GABAB agonist, baclofen also inhibited glucose induced insulin secretion in presence of both 4mM and 20mM glucose. This shows the inhibitory role of GABA and its specific receptor subtypes over insulin synthesis from pancreatic bete-islets. In vitro DNA synthesis studies showed that activation of GABAA receptor by adding muscimol, a specific agonist, inhibited islet DNA synthesis. Also, the addition of baclofen, a specific agonist of GABAB receptor resulted in the stimulation of DNA synthesis.Thus the brain and pancreatic GABAA and GABAB receptor gene expression differentially regulates pancreatic insulin secretion and islet cell proliferation during pancreatic regeneration. This will have immense clinical significance in therapeutic applications in the management of Diabetes mellitus.

Dopamine Receptor Subtypes,IP3, cAMP and cGMP Functional Regulation in Parkinsonism Induced by Unilateral Infusion of Rotenone in Rats: Recovery with Bone Marrow Cells,Serotonin and GABA Supplementation

In the present study, the effects of 5-HT, GABA and Bone Marrow Cells infused intranigrally to substantia nigra individually and in combinations on unilateral rotenone infused Parkinsonism induced rats. Scatchard analysis of DA, DA D1 and D2 receptors in the corpus striatum, cerebral cortex, cerebellum, brain stem and hippocampus showed a significant increase in the Brain regions of rotenone infused rat compared to control. Real Time PCR amplification of DA D1, D2, Bax and ubiquitin carboxy-terminal hydrolase were up regulated in the brain regions of rotenone infused rats compared to control. Gene expression studies of -Synuclien, cGMP and Cyclic AMP response element-binding protein showed a significant down regulation in Rotenone infused rats compared to control. Behavioural studies were carried out to confirm the biochemical and molecular studies.Our study demonstrated that BMC administration alone cannot reverse the above said molecular changes occurring in PD rat. 5-HT and GABA acting through their specific receptors in combination with bone marrow cells play a crucial role in the functional recovery of PD rats. 5-HT, GABA and Bone marrow cells treated PD rats showed significant reversal to control in DA receptor binding and gene expression. 5-HT and GABA have co-mitogenic property. Proliferation and differentiation of cells re-establishing the connections in Parkinson's disease facilitates the functional recovery. Thus, it is evident that 5-HT and GABA along with BMC to rotenone infused rats renders protection against oxidative, related motor and cognitive deficits which makes them clinically significant for cellbased therapy. The BMC transformed to neurons when co-transplanted with 5-HT and GABA which was confirmed with PKH2GL and nestin. These newly formed neurons have functional significance in the therapeutic recovery of Parkinson’s disease.

Regulation of GABA(A) and glutamate receptor expression, synaptic facilitation and long-term potentiation in the hippocampus of prion mutant mice

Background: Prionopathies are characterized by spongiform brain degeneration, myoclonia, dementia, and periodic electroencephalographic (EEG) disturbances. The hallmark of prioniopathies is the presence of an abnormal conformational isoform (PrP(sc)) of the natural cellular prion protein (PrP(c)) encoded by the Prnp gene. Although several roles have been attributed to PrP(c), its putative functions in neuronal excitability are unknown. Although early studies of the behavior of Prnp knockout mice described minor changes, later studies report altered behavior. To date, most functional PrP(c) studies on synaptic plasticity have been performed in vitro. To our knowledge, only one electrophysiological study has been performed in vivo in anesthetized mice, by Curtis and coworkers. They reported no significant differences in paired-pulse facilitation or LTP in the CA1 region after Schaffer collateral/commissural pathway stimulation. Principal Findings: Here we explore the role of PrP(c) expression in neurotransmission and neural excitability using wild-type, Prnp -/- and PrP(c)-overexpressing mice (Tg20 strain). By correlating histopathology with electrophysiology in living behaving mice, we demonstrate that both Prnp -/- mice but, more relevantly Tg20 mice show increased susceptibility to KA, leading to significant cell death in the hippocampus. This finding correlates with enhanced synaptic facilitation in paired-pulse experiments and hippocampal LTP in living behaving mutant mice. Gene expression profiling using Illumina microarrays and Ingenuity pathways analysis showed that 129 genes involved in canonical pathways such as Ubiquitination or Neurotransmission were co-regulated in Prnp -/- and Tg20 mice. Lastly, RT-qPCR of neurotransmission-related genes indicated that subunits of GABA(A) and AMPA-kainate receptors are co-regulated in both Prnp -/- and Tg20 mice. Conclusions/Significance: Present results demonstrate that PrP(c) is necessary for the proper homeostatic functioning of hippocampal circuits, because of its relationships with GABA(A) and AMPA-Kainate neurotransmission. New PrP(c) functions have recently been described, which point to PrP(c) as a target for putative therapies in Alzheimer's disease. However, our results indicate that a "gain of function" strategy in Alzheimer's disease, or a "loss of function" in prionopathies, may impair PrP(c) function, with devastating effects. In conclusion, we believe that present data should be taken into account in the development of future therapies.

Cholinergic receptor subtypes functional regulation in spinal cord injured monoplegic rats

The present study deals with the Cholinergic Receptor subtypes functional regulation in spinal cord injured monoplegic rats: Effect of 5-HT GABA and bone marrow cells.Spinal cord injury causes permanent and irrevocable motor deficits and neurodegeneration. Disruption of the spinal cord leads to diminished transmission of descending control from the brain to motor neurons and ascending sensory information. Behavioural studies showed deficits in motor control and coordination in SCI rats. Cholinergic system plays an important role in SCI, the evaluation of which provides valuable insight on the underlying mechanisms of motor deficit that occur during SCI. The cholinergic transmission was studied by assessing the muscarinic and nicotinic receptors; cholinergic enzymes- ChAT and AChE; second messenger enzyme PLC; transcription factor CREB and second messengers - IP3, cAMP and cGMP. We observed a decrease in the cholinergic transmission in the brain and spinal cord of SCI rats. The disrupted cholinergic system is the indicative of motor deficit and neuronal degeneration in the spinal cord and brain regions. SCI mediated oxidative stress and apoptosis leads to neuronal degeneration in SCI rats. The decreased expression of anti oxidant enzymes – SOD, GPx and neuronal cell survival factors - BDNF, GDNF, IGF-1, Akt and cyclin D2 along with increased expression of apoptotic factors – Bax, caspase-8, TNFa and NF-kB augmented the neuronal degeneration in SCI condition. BMC administration in combination with 5-HT and GABA in SCI rats showed a reversal in the impaired cholinergic neurotransmission and reduced the oxidative stress and apoptosis. It also enhanced the expression of cell survival factors in the spinal cord region. In SCI rats treated with 5-HT and GABA, the transplanted BMC expressed NeuN confirming that 5-HT and GABA induced the differentiation and proliferation of BMC to neurons in the spinal cord. Neurotrophic factors and anti-apoptotic elements in SCI rats treated with 5-HT and GABA along with BMC rendered neuroprotective effects accompanied by improvement in behavioural deficits. This resulted in a significant reversal of altered cholinergic neurotransmission in SCI. The restorative and neuro protective effects of BMC in combination with 5-HT and GABA are of immense therapeutic significance in the clinical management of SCI.

Serotonin receptor subtypes functional regulation and oxidative stress mediated apoptosis in 6-hydroxydopamine lesioned Parkinsonian rats

Parkinson’s disease is a chronic progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the SNpc resulting in severe motor impairments. Serotonergic system plays an important regulatory role in the pathophysiology of PD in rats, the evaluation of which provides valuable insight on the underlying mechanisms of motor, cognitive and memory deficits in PD. We observed a decrease in 5-HT content in the brain regions of 6-OHDA infused rat compared to control. The decreased 5-HT content resulted in a decrease of total 5-HT, 5-HT2A receptors and 5-HTT function and an increase of 5-HT2C receptor function. 5-HT receptor subtypes - 5-HT2A and 5-HT2C receptors have differential regulatory role on the modulation of DA neurotransmission in different brain regions during PD. Our observation of impaired serotonergic neurotransmission in SNpc, corpus striatum, cerebral cortex, hippocampus, cerebellum and brain stem demonstrate that although PD primarily results from neurodegeneration in the SNpc, the associated neurochemical changes in other areas of the brain significantly contributes to the different motor and non motor symptoms of PD. The antioxidant enzymes – SOD, CAT and GPx showed significant down regulation which indicates increased oxidative damage resulting in neurodegeneration. We also observed an increase in the level of lipid peroxidation. Reduced expression of anti-apoptotic Akt and enhanced expression of NF-B resulting from oxidative stress caused an activation of caspase-8 thus leading the cells to neurodegeneration by apoptosis. BMC administration in combination with 5-HT and GABA to PD rats showed reversal of the impaired serotonergic neurotransmission and oxidative stress mediated apoptosis. The transplanted BMC expressed NeuN confirming that 5-HT and GABA induced the differentiation and proliferation of BMC to neurons in the SNpc along with an increase in DA content and an enhanced expression of TH. Neurotrophic factors – BDNF and GDNF rendered neuroprotective effects accompanied by improvement in behavioural deficits indicating a significant reversal of altered dopaminergic and serotonergic neurotransmission in PD. The restorative and neuroprotective effects of BMC in combination with 5-HT and GABA are of immense therapeutic significance in the clinical management of PD.

Withania somnitera and withanolide a mediated restoration of AMPA and NMDA receptor function in pilocarpine induced temporal lobe epilepsy

The onset of spontaneous seizures triggers a cascade of molecular and cellular events that eventually leads to neuronal injury and cognitive decline. The present study investigated the effect of Withania somnifera (WS) root extract and Withanolide A (WA) in restoring behavioural deficit by inhibiting oxidative stress induced alteration in glutamergic neurotransmission. The subdued performance in behavioural tests shows impaired motor coordination and memory. Histopathological investigations revealed significant neuronal loss in hippocampus of epileptic rats indicating glutamate mediated excitotoxicity. The treatment with WS and WA restored behavioural deficit and ameliorated neuronal loss. An altered redox homeostasis leading to oxidative stress is a hallmark of TLE. The antioxidant potential was afflicted in epileptic rats, evident from altered activity of SOD and CAT, down regulation of SOD and GPX expression and enhanced lipid peroxidation. The antioxidant property of WS and WA restored altered antioxidant capacity. Alteration in GDH activity and down regulation of GLAST expression resulted in enhanced glutamate content in the brain regions. The metabolism of glutamate was altered in the form of down regulated GAD expression. The alteration in synthesis, transport and metabolism resulted in further increase of the glutamate concentration at the synapse leading to glutamate mediated excitotoxicity. The decreased NMDA and AMPA receptor binding and down regulated NMDA R1, NMDA 2B and AMPA (GluR2) mRNA expression indicated altered glutamergic receptor function. The treatment with WS and WA reversed altered glutamergic receptor function, synthesis, transport and metabolism. The enhanced levels of second messenger IP3 responsible for Ca2+ mediated toxicity was reversed after treatment with WS and WA. Neurotoxics concentration of glutamate resulted in up regulation of pro apoptotic factors Bax and Caspase 8 and down regulation of anti apoptotic factor Akt resulting in neuronal death. The treatment with WS and WA resulted in activation of Akt and down regulation of Bax and caspase 8 leading to blocking of apoptotic pathway. The treatment with WS and WA resulted in reduced seizure frequency and amelioration of associated alterations suggesting the therapeutic role of Withania somnifera in temporal lobe epilepsy

Serotonin Receptor Gene Expression And Insulin Function In Streptozotocin Induced Diabetic Rats

Recent studies have established a fimctional correlation of serotonergic and adrenergic function in the brain regions with insulin secretion in diabetic rats (Vahabzadeh et al., 1995). Administration of 5-HT”. agonist 8-OH-DPAT to conscious rats caused an increase in blood glucose level. This increase in blood glucose is due to inhibition of insulin secretion by increased circulating EPI (Chaouloff et al., 1990a; Chaouloff et al., 1990d; Chaoulo1T& Jeanrenaud, 1987). The increase in EPI is brought about by increased sympathetic stimulation. This increase can lead to increased sympatho-medullary stimulation thereby inhibiting insulin release (Bauhelal & Mir, 1993, Bauhelal & Mir, 1990a; Chaouloffet al., 1990d). Also, studies have shown that Gi protein in the liver has been decreased in diabetes which will increase gluconeogenesis and glycogenolysis thereby causing hyperglycaemia (Pennington, 1987). Serotonergic control is suggested to exert different effects on insulin secretion according to the activation of different receptor subclasses (Pontiroli et al., 1975). In addition to this mechanism, the secretion of insulin is dependent on the turnover ratio of endogenous 5-hydroxy tryptophan (5-HTP) to 5-HT in the pancreatic islets (Jance er al., 1980). The reports so far stated does not explain the complete mechanism and the subclass of 5-HT receptors whose expression regulate insulin secretion in a diabetic state. Also, there is no report of a direct regulation of insulin secretion by 5-HT from the pancreatic islets even though there are reports stating that the pancreatic islets is a rich source of 5-HT (Bird et al., 1980). Therefore, in the present study the mechanism by which 5-HT and its receptors regulate insulin secretion from pancreatic [3-cells was investigated. Our results led to the following hypotheses by which 5-HT and its receptors regulate the insulin secretion.

Análisis de polimorfismos genéticos del receptor beta-2 adrenérgico en pacientes pediátricos asmáticos y controles sanos en una muestra de la ciudad de Bogotá

El asma bronquial es una enfermedad inflamatoria crónica, se asocia a hiperrespuesta de la vía aérea, la cual lleva a episodios recurrentes de sibilancias, tos y disnea. La entidad se ha correlacionado con una gran variedad de genes involucrados en su fisiopatología, dentro de los cuales se encuentran genes localizados en el cromosoma 5 (5q23-31), como el del Receptor ß2 Adrenérgico (RB2A). En el presente trabajo se realizó una estimación de las frecuencias de los polimorfismos Arg16Gly, Gln27Glu y Thr164Ile de este receptor, y se estudió la relación existente entre los diferentes polimorfismos y asma, así como su relación con respecto a la severidad de la enfermedad, finalmente se estimó la relación de los haplotipos conformados por estos tres polimorfismos y su asociación con la enfermedad y severidad del fenotipo asmático.

Functional studies of the deubiquitinating enzymes USP19, USP4 and UCH-L1

El marcaje de proteínas con ubiquitina, conocido como ubiquitinación, cumple diferentes funciones que incluyen la regulación de varios procesos celulares, tales como: la degradación de proteínas por medio del proteosoma, la reparación del ADN, la señalización mediada por receptores de membrana, y la endocitosis, entre otras (1). Las moléculas de ubiquitina pueden ser removidas de sus sustratos gracias a la acción de un gran grupo de proteasas, llamadas enzimas deubiquitinizantes (DUBs) (2). Las DUBs son esenciales para la manutención de la homeostasis de la ubiquitina y para la regulación del estado de ubiquitinación de diferentes sustratos. El gran número y la diversidad de DUBs descritas refleja tanto su especificidad como su utilización para regular un amplio espectro de sustratos y vías celulares. Aunque muchas DUBs han sido estudiadas a profundidad, actualmente se desconocen los sustratos y las funciones biológicas de la mayoría de ellas. En este trabajo se investigaron las funciones de las DUBs: USP19, USP4 y UCH-L1. Utilizando varias técnicas de biología molecular y celular se encontró que: i) USP19 es regulada por las ubiquitin ligasas SIAH1 y SIAH2 ii) USP19 es importante para regular HIF-1α, un factor de transcripción clave en la respuesta celular a hipoxia, iii) USP4 interactúa con el proteosoma, iv) La quimera mCherry-UCH-L1 reproduce parcialmente los fenotipos que nuestro grupo ha descrito previamente al usar otros constructos de la misma enzima, y v) UCH-L1 promueve la internalización de la bacteria Yersinia pseudotuberculosis.

"Refined mapping of a quantitative trait locus on chromosome 1 responsible for mouse embryonic death"

Recurrent spontaneous abortion (RSA) is defined as the loss of three or more consecutive pregnancies during the first trimester of embryonic intrauterine development. This kind of human infertility is frequent among the general population since it affects 1 to 5% of women. In half of the cases the etiology remains unelucidated. In the present study, we used interspecific recombinant congenic mouse strains (IRCS) in the aim to identify genes responsible for embryonic lethality. Applying a cartographic approach using a genotype/phenotype association, we identified a minimal QTL region, of about 6 Mb on chromosome 1, responsible for a high rate of embryonic death (,30%). Genetic analysis suggests that the observed phenotype is linked to uterine dysfunction. Transcriptomic analysis of the uterine tissue revealed a preferential deregulation of genes of this region compared to the rest of the genome. Some genes from the QTL region are associated with VEGF signaling, mTOR signaling and ubiquitine/proteasome-protein degradation pathways. This work may contribute to elucidate the molecular basis of a multifactorial and complex human disorder as RSA.

Refined mapping of a quantitative trait locus on chromosome 1 responsible for mouse embryonic death

Recurrent spontaneous abortion (RSA) is defined as the loss of three or more consecutive pregnancies during the first trimester of embryonic intrauterine development. This kind of human infertility is frequent among the general population since it affects 1 to 5% of women. In half of the cases the etiology remains unelucidated. In the present study, we used interspecific recombinant congenic mouse strains (IRCS) in the aim to identify genes responsible for embryonic lethality. Applying a cartographic approach using a genotype/phenotype association, we identified a minimal QTL region, of about 6 Mb on chromosome 1, responsible for a high rate of embryonic death (similar to 30%). Genetic analysis suggests that the observed phenotype is linked to uterine dysfunction. Transcriptomic analysis of the uterine tissue revealed a preferential deregulation of genes of this region compared to the rest of the genome. Some genes from the QTL region are associated with VEGF signaling, mTOR signaling and ubiquitine/proteasome-protein degradation pathways. This work may contribute to elucidate the molecular basis of a multifactorial and complex human disorder as RSA.

Modelo integrador para las rutas de señalización diferencial del receptor ionotrópico de glutamato activado por el N-metil-D-aspartato

El receptor ionotrópico de glutamato activado por N-metil-D-aspartato (iGluR-NMDA) es un complejo macromolecular heteromultimérico constituido por entre 3 y 5 subunidades de tres diferentes tipos, a saber: NR1, NR2A-D y NR3A y B. Se ha demostrado su participación activa en prácticamente todos los procesos fisiológicos, patológicos e intermediarios de efectos farmacológicos que ocurren en las células de tejidos excitables, inclusive se ha reportado su presencia en otros tejidos no excitables. En el sistema nervioso central (SNC) participa en los procesos de aprendizaje, memoria, plasticidad, diferenciación, migración de la célula neural y apoptosis. Además, en los eventos de índole farmacológica se ha demostrado su intervención en excitotoxicidad, drogadicción y alcoholismo. Surge entonces la pregunta de cómo un mismo complejo macromolecular puede participar en tantos y tan diversos procesos. La revisión de literatura en la que se demuestra la interacción del iGluR-NMDA con proteínas de señalización, soporte, adaptadoras, moduladoras, de adhesión celular, de citoesqueleto y enzimas reporta un conjunto de más de 160 moléculas que participan en las cascadas que generan las señales a diferentes niveles de interacción y con diferentes sustratos. En este artículo se presenta un modelo predictivo estructural y funcional que permite distinguir, por lo menos, tres rutas diferenciadas de señalización.