Taurine Promotes Differentiation and Maturation of Neural Stem/Progenitor Cells from the Subventricular Zone via Activation of GABAA Receptors.

Neurogenesis, the formation of new neurons in the brain, occurs throughout the lifespan in the subgranular zone of the dentate gyrus and subventricular zone (SVZ) lining the lateral ventricles of the mammal brain. In this process, gamma-aminobutyric acid (GABA) and its ionotropic receptor, the GABAA receptor (GABAAR), play a critical role in the proliferation, differentiation, and migration process of neural stem/progenitor cells (NPC). Taurine, a non-essential amino acid widely distributed throughout the central nervous system, increases the proliferation of SVZ progenitor cells by a mechanism that may involve GABAAR activation. Therefore, we characterized the effects of taurine on the differentiation process of NPC expressing GABAAR. Preincubation of NPC-SVZ with taurine increased microtubule-stabilizing proteins assessed with the doublecortin assay. Taurine, like GABA, stimulated a neuronal-like morphology of NPC-SVZ and increased the number and length of primary, secondary, and tertiary neurites compared with control NPC of the SVZ. Furthermore, neurite outgrowth was prevented when simultaneously incubating cells with taurine or GABA and the GABAAR blocker, picrotoxin. Patch-clamp recordings revealed a series of modifications in the NPCs' passive and active electrophysiological properties exposed to taurine, including regenerative spikes with kinetic properties similar to the action potentials of functional neurons.

A synergy of the nutritional additives taurine and silymarin in salmon farming: evaluation with the CHSE-214 cellular model.

The use of additives in the feed industry for producing fish has become the focus of constant change and research. The formulation of a product as a feeding strategy leads to the use of more than one molecule with particular characteristics to seek a synergistic effect when they are administered in the food. The application of taurine and silymarin in the salmon farming industry needs the exploration of the synergistic effects. For this study, we evaluated the effects of various concentrations of additives in the cell line CHSE-214 of Oncorhynchus tshawytscha. The cells were exposed to increasing concentrations of hydrogen peroxide as an oxidizing agent and were then given treatments of taurine, silymarin or both additives together. Our results indicate that the molecules had separate antioxidant effects, and the taurine treatment reached the highest number of cells per area at a dose of 100 ppm. However, if the cells were treated together at 100 ppm, silymarin achieved outstanding effects. However, when the treatment with both molecules was increased to 500 ppm of taurine, the effect was blocked, and the treatment acted as an antagonist. Our data indicate that the formulation of diets must be rigorously carried out, especially for determining the doses to be used to generate synergy among antioxidant additives and to reduce the effect of antagonism between the additives. Likewise, the use of cell lines is a strategy to evaluate the mechanisms of action for additives that are used in the development of diets for the salmon industry.

Differential modulation of human GABAC-ρ1 receptor by sulfur-containing compounds structurally related to taurine.

BACKGROUND: The amino acid taurine (2-Aminoethanesulfonic acid) modulates inhibitory neurotransmitter receptors. This study aimed to determine if the dual action of taurine on GABAC-ρ1R relates to its structure. To address this, we tested the ability of the structurally related compounds homotaurine, hypotaurine, and isethionic acid to modulate GABAC-ρ1R. RESULTS: In Xenopus laevis oocytes, hypotaurine and homotaurine partially activate heterologously expressed GABAC-ρ1R, showing an increment in its deactivation time with no changes in channel permeability, whereas isethionic acid showed no effect. Competitive assays suggest that hypotaurine and homotaurine compete for the GABA-binding site. In addition, their effects were blocked by the ion-channel blockers picrotixin and Methyl(1,2,5,6-tetrahydropyridine-4-yl) phosphinic acid. In contrast to taurine, co-application of GABA with hypotaurine or homotaurine revealed that the dual effect is present separately for each compound: hypotaurine modulates positively the GABA current, while homotaurine shows a negative modulation, both in a dose-dependent manner. Interestingly, homotaurine diminished hypotaurine-induced currents. Thus, these results strongly suggest a competitive interaction between GABA and homotaurine or hypotaurine for the same binding site. "In silico" modeling confirms these observations, but it also shows a second binding site for homotaurine, which could explain the negative effect of this compound on the current generated by GABA or hypotaurine, during co-application protocols. CONCLUSIONS: The sulfur-containing compounds structurally related to taurine are partial agonists of GABAC-ρ1R that occupy the agonist binding site. The dual effect is unique to taurine, whereas in the case of hypotaurine and homotaurine it presents separately; hypotaurine increases and homotaurine decreases the GABA current.

Characterization of an outward rectifying chloride current of Xenopus tropicalis oocytes.

Here, we describe an outward rectifying current in Xenopus tropicalis oocytes that we have called xtClC-or. The current has two components; the major component is voltage activated and independent of intracellular or extracellular Ca(2+), whereas the second is a smaller component that is Ca(2+) dependent. The properties of the Ca(2+)-independent current, such as voltage dependence and outward rectification, resemble those of ClC anion channels/transporters. This current is sensitive to NPPB and NFA, insensitive to 9AC and DIDS, and showed a whole-cell conductance sequence of SCN(-)>I(-)>Br(-)>CI(-). RT-PCR revealed the expression in oocytes of ClC-2 to ClC-7, and major reductions of current amplitudes were observed when a ClC-5 antisense oligonucleotide was injected into oocytes. The Ca(2+)-dependent component was abated after injection of 10mM BAPTA or EGTA, whereas 10mMMg(2+) inhibited the current to 26±3.1%. This component was blocked by 9-AC, NFA, and NPPB, whereas DIDS did not elicit any evident effect. The ion sequence selectivity was SCN=I(-)>Br(-)>Cl(-). To try to determine the molecular identity that gives rise to this component we assessed by RT-PCR the expression of the Ca(2+)-dependent Cl(-) channel TMEM16A, which was found to be present in the oocytes. However, injection of antisense TMEM16A oligonucleotides did not inhibit the transient outward current. This result fits well with the electrophysiological data. Together, these results suggest that ClC-5 is a major, but not the sole channel responsible for this outwardly rectifying Cl(-) current.

The bidirectional role of GABAA and GABAB receptors during the differentiation process of neural precursor cells of the subventricular zone.

The intricate process of neuronal differentiation integrates multiple signals to induce transcriptional, morphological, and electrophysiological changes that reshape the properties of neural precursor cells during their maturation and migration process. An increasing number of neurotransmitters and biomolecules have been identified as molecular signals that trigger and guide this process. In this sense, taurine, a sulfur-containing, non-essential amino acid widely expressed in the mammal brain, modulates the neuronal differentiation process. In this study, we describe the effect of taurine acting via the ionotropic GABAA receptor and the metabotropic GABAB receptor on the neuronal differentiation and electrophysiological properties of precursor cells derived from the subventricular zone of the mouse brain. Taurine stimulates the number of neurites and favors the dendritic complexity of the neural precursor cells, accompanied by changes in the somatic input resistance and the strength of inward and outward membranal currents. At the pharmacological level, the blockade of GABAA receptors inhibits these effects, whereas the stimulation of GABAB receptors has no positive effects on the taurine-mediated differentiation process. Strikingly, the blockade of the GABAB receptor with CGP533737 stimulates neurite outgrowth, dendritic complexity, and membranal current kinetics of neural precursor cells. The effects of taurine on the differentiation process involve Ca2+ mobilization and the activation of intracellular signaling cascades since chelation of intracellular calcium with BAPTA-AM, and inhibition of the CaMKII, ERK1/2, and Src kinase inhibits the neurite outgrowth of neural precursor cells of the subventricular zone.

Glia as a key factor in cell volume regulation processes of the central nervous system.

Brain edema is a pathological condition with potentially fatal consequences, related to cerebral injuries such as ischemia, chronic renal failure, uremia, and diabetes, among others. Under these pathological states, the cell volume control processes are fully compromised, because brain cells are unable to regulate the movement of water, mainly regulated by osmotic gradients. The processes involved in cell volume regulation are homeostatic mechanisms that depend on the mobilization of osmolytes (ions, organic molecules, and polyols) in the necessary direction to counteract changes in osmolyte concentration in response to water movement. The expression and coordinated function of proteins related to the cell volume regulation process, such as water channels, ion channels, and other cotransport systems in the glial cells, and considering the glial cell proportion compared to neuronal cells, leads to consider the astroglial network the main regulatory unit for water homeostasis in the central nervous system (CNS). In the last decade, several studies highlighted the pivotal role of glia in the cell volume regulation process and water homeostasis in the brain, including the retina; any malfunction of this astroglial network generates a lack of the ability to regulate the osmotic changes and water movements and consequently exacerbates the pathological condition.

Functional impact of serial deletions at the C-terminus of the human GABArho1 receptor.

GABArho1 receptors are formed by homopentameric assemblies that gate a chloride ion-channel upon activation by the neurotransmitter. Very little is known about the structural and functional roles played by the different domains that form each subunit; but one of them, the fourth transmembrane segment (TM4), is known to form a hydrophobic bundle together with three other TM segments that are necessary to stabilize the structure of the receptor. In this study we progressively removed amino acid residues from the C-terminus of the human GABArho1 and studied the functional properties of the receptor mutants expressed in X. laevis oocytes. We found that deletions of up to the last four residues gave rise to receptors that were still functional, generating currents of 3.92 microA for the wt, 5.75 microA for S479X, 1.82 microA for F478X, 0.52 microA for I477X and 0.27 microA for S476X when exposed to 5 microM GABA; surprisingly, the mutant with one residue removed resulted more sensitive to the agonists. Further deletions, up to residue W475, resulted in receptors that did not gate an ion-channel. In addition, deleting the signal sequence, from R2-A15, in the N-terminus produced non-functional receptors. This study reveals that GABArho1 can tolerate removal of several residues that form the fourth transmembrane segment up to a critical point, signaled by W475, beyond which the mutant protein is translated but does not form functional receptors. A comparative study is presented of some electrophysiological and pharmacological properties of the deletion mutants that were able to generate GABA currents.

SARS-CoV-2 and the Eye: A Relationship for a Possible Prognostic Tool in COVID-19 Patients.

PURPOSE: In December 2019 there was the first report about a new viral infection in Wuhan, China. The new virus was taxonomically designed as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing the coronavirus disease 2019 (COVID-19). SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor for cell invasion, which is expressed in different tissues including lungs, small intestine, testicles, kidneys, brain, and the eye. The purpose of this article is to review the available information on the relationship of COVID-19 with the eye, as well as evaluating the possible usefulness of ocular diagnostic tests to help in the diagnosis and/or monitoring of patients with this disease. METHODS: We performed a retrospective review of relevant articles from November 2019 to April 2020. RESULTS: Ocular infection by SARS-CoV-2 is still controversial; nevertheless, the possibility of being a viral reservoir has been suggested, increasing the likelihood of infection. Some reports demonstrated the presence of SARS-CoV-2 in tears, and previously published data suggest a pathological increase of cytokine concentrations in COVID-19 patients; the cytokine release syndrome or cytokine storm contributes to lung and central nervous system damage. The usefulness of tears for the measurement of inflammatory cytokines in various diseases is well known, in particular IL-6, which has been correlated to the severity of COVID-19. CONCLUSION: Considering that the IL-6 signaling cascade may be activated in patients with COVID-19, makes it an excellent target for diagnostic and/or monitoring purposes.

Abnormal N-Glycosylation of Human Lens Epithelial Cells in Type-2 Diabetes May Contribute to Cataract Progression.

PURPOSE: In order to better understand cataract development, we analyzed the glycosylation profile of human lens epithelial cells (HLECs) from anterior lens capsules of type 2 diabetes mellitus (T2DM) and non-diabetic (ND) patients undergoing routine cataract surgery. SETTING: Research Department of the Asociación para Evitar la Ceguera, Hospital "Dr. Luis Sánchez Bulnes", Mexico. DESIGN: Experimental study. METHODS: Evaluation of anterior lens capsules from T2DM and ND patients undergoing phacoemulsification and free from other ocular diseases. RESULTS: Hematoxylin-eosin staining revealed HLECs alterations in T2DM samples. From lectins with different sugar specificities used, concanavalin A showed significant differences, labeling homogeneously both in the cytoplasm and in cell membranes in ND capsules, while in T2DM capsules, in addition to membrane and cytoplasm labeling, there were perinuclear vesicles with high concanavalin A labeling. Two-dimensional gel electrophoresis showed that T2DM patients have a ~65-kDa spot with an isoelectric point of 5.5 with a higher density compared to ND capsules, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed 62% homology with type-1 cytokeratin. Immunohistochemistry using anti-pan cytokeratin antibody revealed co-localization with concanavalin A, and a lectin blot revealed with concanavalin A showed a band of ~65 kDa, a molecular weight that corresponds to human type 1 cytokeratin. CONCLUSION: These results suggest that over-expression of N-glycosidically linked human type 1 cytokeratin may induce capsule disruption and affect selective permeability, allowing the entry of different molecules to the lens that facilitate cataract progression.

Taurine and GABA neurotransmitter receptors, a relationship with therapeutic potential?

Taurine is a ß-amino acid present in high concentrations in different areas of the mammalian central nervous system (CNS). It participates in different physiological processes such as osmoregulation, signal transduction, antioxidant activity, trophic factor activity, modulation of calcium movements and neurotransmission. It is known that taurine is an agonist of GABAA receptors, and their affinity depends of the subunits that conform this receptor. GABA is the main inhibitory neurotransmitter of the CNS and exerts its effect through the activation of two types of specific receptors, called GABAA and GABAB. In the last years, changes in the expression pattern of the GABAA receptors subunits has been related to pathologies, such as epilepsy, depression and alcoholism, among others. This changes in the GABAA receptors conformation might be responsible of the loss in the effectiveness of the different drugs used in clinic protocols. Therefore, considering the physiological properties of taurine and the capacity to interact with GABAA receptors conformed by different subunits combinations, it is clear their great potential for the design of new pharmacological strategies aimed to treat the pathologies where GABA has shown a relevant participation.

Age-Related Macular Degeneration: New Paradigms for Treatment and Management of AMD.

Age-related macular degeneration (AMD) is a well-characterized and extensively studied disease. It is currently considered the leading cause of visual disability among patients over 60 years. The hallmark of early AMD is the formation of drusen, pigmentary changes at the macula, and mild to moderate vision loss. There are two forms of AMD: the "dry" and the "wet" form that is less frequent but is responsible for 90% of acute blindness due to AMD. Risk factors have been associated with AMD progression, and they are taking relevance to understand how AMD develops: (1) advanced age and the exposition to environmental factors inducing high levels of oxidative stress damaging the macula and (2) this damage, which causes inflammation inducing a vicious cycle, altogether causing central vision loss. There is neither a cure nor treatment to prevent AMD. However, there are some treatments available for the wet form of AMD. This article will review some molecular and cellular mechanisms associated with the onset of AMD focusing on feasible treatments for each related factor in the development of this pathology such as vascular endothelial growth factor, oxidative stress, failure of the clearance of proteins and organelles, and glial cell dysfunction in AMD.

Current Anti-Integrin Therapy for Ocular Disease.

The integrin family of cell adhesion molecules mediates homeostasis, signal transduction, and various other interactions between the cell and the extracellular matrix. Integrins are type-1 transmembrane glycoproteins located on the cell surface, widely expressed in leukocytes, which play an important role in the inflammatory pathway. The purpose of this review is to summarize the current state of anti-integrin therapy and to assess ongoing clinical trials in ocular disease. We performed a search on PubMed, CINAHL, and Embase for the published literature available using the MeSH terms: "integrin therapy" and "αLß2," "α4ß1" and "α4ß7," "αvß3," "αvß5," and "αvß1" and/or "ophthalmology," and "clinical trials." We used no language restrictions. We generated searches to account for synonyms of these keywords and MESH headings as follows: (1) "integrin," "therapy," or "treatment"; (2) "clinical trials," "ophthalmology," or "ocular." In addition, the analysis included phase 2 and phase 3 clinical trials with a minimal follow-up of six months. Integrin antagonists have shown their capacity to improve signs and symptoms of patients with dry eye disease, age-related macular degeneration, diabetic macular edema, and vitreomacular traction.

Brain distribution and molecular cloning of the bovine GABA rho1 receptor.

GABA(C) receptors were originally found in the mammalian retina and recent evidence shows that they are also expressed in several areas of the brain, including caudate nucleus, brain stem, pons and corpus callosum. In this study, plasma membranes from the caudate nucleus were microinjected into X. laevis oocytes. This led the oocyte plasma membrane to incorporate functional bicuculline-resistant, Cl(-) conducting bovine GABA receptors, similar to those of the retina. Immunolocalization of the GABA rho1 subunit revealed its expression in bovine neurons in the head of the caudate as well as in the olive, cuneiform and reticular nuclei of the brain stem. The same antibodies failed to show expression in the callosum and pons, where the GABA rho1 mRNA was previously detected. The cloned GABA rho1 sequence predicts a protein with 473 amino acids and 74-93% similarity to other GABA rho1 subunits. Oocytes injected with the cDNA express a non-desensitizing, homomeric receptor with a GABA EC(50)=6.0 microM and a Hill coefficient of 1.8. The results confirm the presence of GABA(C) receptor mRNAs in several areas of the mammalian brain and show that some of these areas express functional GABA rho1 receptors that have the classic GABA(C) receptor characteristics.

Effect of phacoemulsification on intraocular pressure in patients with primary open angle glaucoma and pseudoexfoliation glaucoma.

AIM: To compare the effect of phacoemulsification on intraocular pressure (IOP) in patients with primary open angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXG). METHODS: A retrospective comparative case series conducted at the Glaucoma Department at the Association to Prevent Blindness in Mexico. The study enrolled consecutive patients having phacoemulsification with intraocular lens (IOL) implantation and a diagnosis of POAG or PXG. Data about IOP values and number of glaucoma medications used was collected at baseline, 1, 3, 6 and 12mo postoperatively. RESULTS: The study enrolled 88 patients (88 eyes). After phacoemulsification, there was a statistically significant reduction in IOP values and glaucoma medications use compared to baseline in both POAG and PXG patients (P<0.001). In the POAG group, a 20% decrease in IOP values was evidenced, and a 56.5% reduction in the number of medications used at the one-year follow-up. The PXG group showed a 20.39%, and a 34.46% decrease in IOP and number of medications used, respectively. A significant difference in the mean ΔIOP (postoperative changes in IOP) was evidenced between groups (P=0.005). The reduction of the postsurgical IOP mean values in both groups, the POAG group showed a greater reduction in IOP values compared to the PXG group. CONCLUSION: In both types of glaucoma, phacoemulsification cataract surgery can result in a significant IOP reduction (20%) over a 12mo follow-up period. The number of medications used is also significantly reduced up to 12mo after surgery, especially in the PXG group.

Amyloid pore-channel hypothesis: effect of ethanol on aggregation state using frog oocytes for an Alzheimer's disease study.

Alzheimer's disease severely compromises cognitive function. One of the mechanisms to explain the pathology of Alzheimer's disease has been the hypotheses of amyloid-pore/channel formation by complex Aß-aggregates. Clinical studies suggested the moderate alcohol consumption can reduces probability developing neurodegenerative pathologies. A recent report explored the ability of ethanol to disrupt the generation of complex Aß in vitro and reduce the toxicity in two cell lines. Molecular dynamics simulations were applied to understand how ethanol blocks the aggregation of amyloid. On the other hand, the in silico modeling showed ethanol effect over the dynamics assembling for complex Aß-aggregates mediated by break the hydrosaline bridges between Asp 23 and Lys 28, was are key element for amyloid dimerization. The amyloid pore/channel hypothesis has been explored only in neuronal models, however recently experiments suggested the frog oocytes such an excellent model to explore the mechanism of the amyloid pore/channel hypothesis. So, the used of frog oocytes to explored the mechanism of amyloid aggregates is new, mainly for amyloid/pore hypothesis. Therefore, this experimental model is a powerful tool to explore the mechanism implicates in the Alzheimer's disease pathology and also suggests a model to prevent the Alzheimer's disease pathology.

Diferencias intra-especie en respuesta al estrés: Hacia enfoques traslacionales / Intra-specie differences in response to stress: Looking for translational view

Resumen: El estrés produce la sobreactivación del eje HPA y sistema neuroendocrino. Se ha mostrado que existe daño en estructuras relacionadas con el procesamiento emocional (amígdala) aprendizaje (hipocampo), toma de decisiones y prospección (corteza prefrontal). Sin embargo, se generalizan los efectos del estrés sin ponderar el tipo de estrés (crónico o agudo), duración, especie, etc. Esto permite que hallazgos se contrapongan a nivel cortical, neuroquímico, hormonal y conductual. El objetivo fue evaluar los efectos del estrés crónico impredecible (ECI) en diferentes cepas de ratas y sus efectos inmediatos o a largo plazo. Se utilizaron ratas macho Wistar, Wistar Kyoto y SHR en condiciones estándar de laboratorio. Se aplicó una batería de ECI y una batería de evaluación conductual para evaluar efectos previos, agudos y crónicos. La cepa Wistar Kyoto muestra deficiencias previas a la exposición. La cepa SHR muestra mayor movilidad y sesgos atencionales, lo que produce un efecto que perdura a largo plazo. La cepa Wistar muestra una gran capacidad de adaptación ya que aunque se observaron deficiencias inmediatamente después de la exposición al estrés, éstas se recuperan e largo plazo. Se infiere que las precondiciones de los sujetos podrían funcionar como biomarcadores y poder prevenir padecimientos relacionados al estrés.

Abstract: Stress produces the over activation of the Hypothalamus Pituitary Adrenal axis (HPA) and the neuroendocrine system. It has been shown that it could damage structures related with the emotional processing (amygdala), learning and memory (Hippocampus), decision making and prospection (prefrontal cortex). However, the stress affects are generalized without weighting all the elements related with this conditions, for example the kind of stress stimuli (acute or chronic), duration, species, etc. This allowed that some findings it will go against each other in relation to cerebral cortex function, neurochemical, hormonal and behavioral. The main porpoise of this research was to evaluate the effects of the unpredictable chronic stress on several rat strains (Wistar, Wistar Kyoto and SHR) and its immediate effects or in long term so. Wistar, Wistar Kyoto and SHR rats were used. All animals were housed in standard laboratory conditions and we follow the international guide for use and care of laboratory animals. The subjects were exposed to the Chronic Unpredictable Stress Battery (CUSB) and to evaluate the stress effects all the subjects were evaluated with a Battery of Behavioral Evaluation to find the previous, immediate or the long-term effects of CUSB exposition. The Wistar Kyoto strain showed deficits before the stress exposure. Whereas the SHR rats showed more mobility and poor attention which produces a long-term effect. The Wistar strain show a high adaptation to the adverse conditions because until the animals showed strong effects immediately after the stress exposure they showed a good recovery in the long term. In conclusion we can asseverate that the preconditions in every strain plays a major role in the stress response and that preconditions it could be used as biomarkers and in that way infer if the subjects are more susceptible to suffer high stress or some other related disease.

Functional and structural effects of amyloid-ß aggregate on Xenopus laevis oocytes.

Xenopus laevis oocytes exposed to amyloid-ß aggregate generated oscillatory electric activity (blips) that was recorded by two-microelectrode voltage-clamp. The cells exhibited a series of "spontaneous" blips ranging in amplitude from 3.8 ± 0.9 nA at the beginning of the recordings to 6.8 ± 1.7 nA after 15 min of exposure to 1 µM aggregate. These blips were similar in amplitude to those induced by the channel-forming antimicrobial agents amphotericin B (7.8 ± 1.2 nA) and gramicidin (6.3 ± 1.1 nA). The amyloid aggregate-induced currents were abolished when extracellular Ca(2+) was removed from the bathing solution, suggesting a central role for this cation in generating the spontaneous electric activity. The amyloid aggregate also affected the Ca(2+)-dependent Cl(-) currents of oocytes, as shown by increased amplitude of the transient-outward chloride current (T(out)) and the serum-activated, oscillatory Cl(-) currents. Electron microcopy revealed that amyloid aggregate induced the dissociation of the follicular cells that surround the oocyte, thus leading to a failure in the electro-chemical communication between these cells. This was also evidenced by the suppression of the oscillatory Ca(2+)-dependent ATP-currents, which require proper coupling between oocytes and the follicular cell layer. These observations, made using the X. laevis oocytes as a versatile experimental model, may help to understand the effects of amyloid aggregate on cellular communication.

Dopamine and serotonin modulate human GABAρ1 receptors expressed in Xenopus laevis oocytes.

GABAρ1 receptors are highly expressed in bipolar neurons of the retina and to a lesser extent in several areas of the central nervous system (CNS), and dopamine and serotonin are also involved in the modulation of retinal neural transmission. Whether these biogenic amines have a direct effect on ionotropic GABA receptors was not known. Here, we report that GABAρ1 receptors, expressed in X. laevis oocytes, were negatively modulated by dopamine and serotonin and less so by octopamine and tyramine. Interestingly, these molecules did not have effects on GABA(A) receptors. 5-Carboxamido-tryptamine and apomorphine did not exert evident effects on any of the receptors. Schild plot analyses of the inhibitory actions of dopamine and serotonin on currents elicited by GABA showed slopes of 2.7 ± 0.3 and 6.1 ± 1.8, respectively, indicating a noncompetitive mechanism of inhibition. The inhibition of GABAρ1 currents was independent of the membrane potential and was insensitive to picrotoxin, a GABA receptor channel blocker and to the GABAρ-specific antagonist (1,2,5,6-tetrahydropyridine-4-yl)methyl phosphinic acid (TPMPA). Dopamine and serotonin changed the sensitivity of GABAρ1 receptors to the inhibitory actions of Zn(2+). In contrast, La(3+) potentiated the amplitude of the GABA currents generated during negative modulation by dopamine (EC(50) 146 µM) and serotonin (EC(50) 196 µM). The functional role of the direct modulation of GABAρ receptors by dopamine and serotonin remains to be elucidated; however, it may represent an important modulatory pathway in the retina, where GABAρ receptors are highly expressed and where these biogenic amines are abundant.