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Gastrointestinal (GI) B cells and plasma cells (PCs), critical to mucosal homeostasis, play an important role in the host response to HIV-1 infection. Here, high resolution mapping of human B cells and PCs from colon and ileum during both viremic and suppressed HIV-1 infection identified a significant reduction in germinal center (GC) B cells and Follicular Dendritic Cells (FDCs) during HIV-1 viremia. Further, IgA + PCs, the major cellular output of intestinal GCs were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling persisted in antiretroviral therapy (ART) treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations associated with changes in intestinal microbiome composition and systemic inflammation. Herein, we highlight a key immune defect in the GI mucosa due to HIV-1 viremia, with major implications. One Sentence Summary: Major perturbations in intestinal GC dynamics in viremic HIV-1 infection relate to reduced IgA + plasma cells, systemic inflammation and microbiota changes.
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BACKGROUND & AIMS: Better biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin αvß6 (anti-αvß6) autoantibodies have been described in patients with UC. We tested for the presence of anti-αvß6 antibodies in the preclinical phase of UC and studied their association with disease-related outcomes after diagnosis. METHODS: Anti-αvß6 autoantibodies were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense preclinical cohort (PREDICTS [Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects]). In a distinct, external validation cohort (Crohn's and Colitis Canada Genetic Environmental Microbial project cohort), we tested 12 pre-UC subjects and 49 matched controls. Furthermore, anti-αvß6 autoantibodies were measured in 2 incident UC cohorts (COMPASS [Comprehensive Care for the Recently Diagnosed IBD Patients], n = 55 and OSCCAR [Ocean State Crohn's and Colitis Area Registry], n = 104) and associations between anti-αvß6 autoantibodies and UC-related outcomes were defined using Cox proportional hazards model. RESULTS: Anti-αvß6 autoantibodies were significantly higher among individuals who developed UC compared with controls up to 10 years before diagnosis in PREDICTS. The anti-αvß6 autoantibody seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 time points. Anti-αvß6 autoantibodies predicted UC development with an area under the curve of at least 0.8 up to 10 years before diagnosis. The presence of anti-αvß6 autoantibodies in preclinical UC samples was validated in the GEM cohort. Finally, high anti-αvß6 autoantibodies was associated with a composite of adverse UC outcomes, including hospitalization, disease extension, colectomy, systemic steroid use, and/or escalation to biologic therapy in recently diagnosed UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.
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Colite Ulcerativa , Colite , Doença de Crohn , Humanos , Colite Ulcerativa/tratamento farmacológico , Autoanticorpos , Proteômica , Doença de Crohn/tratamento farmacológico , Biomarcadores , Colite/complicaçõesRESUMO
Gastrointestinal symptoms are common in COVID-19 patients but the nature of the gut immune response to SARS-CoV-2 remains poorly characterized, partly due to the difficulty of obtaining biopsy specimens from infected individuals. In lieu of tissue samples, we measured cytokines, inflammatory markers, viral RNA, microbiome composition, and antibody responses in stool samples from a cohort of 44 hospitalized COVID-19 patients. SARS-CoV-2 RNA was detected in stool of 41% of patients and more frequently in patients with diarrhea. Patients who survived had lower fecal viral RNA than those who died. Strains isolated from stool and nasopharynx of an individual were the same. Compared to uninfected controls, COVID-19 patients had higher fecal levels of IL-8 and lower levels of fecal IL-10. Stool IL-23 was higher in patients with more severe COVID-19 disease, and we found evidence of intestinal virus-specific IgA responses associated with more severe disease. We provide evidence for an ongoing humeral immune response to SARS-CoV-2 in the gastrointestinal tract, but little evidence of overt inflammation.
Assuntos
COVID-19 , Fezes , Microbioma Gastrointestinal , Nasofaringe/virologia , RNA Viral/isolamento & purificação , Idoso , Biomarcadores/metabolismo , COVID-19/epidemiologia , COVID-19/imunologia , Estudos de Coortes , Citocinas/metabolismo , Fezes/virologia , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque/epidemiologia , SARS-CoV-2/isolamento & purificaçãoRESUMO
BACKGROUND & AIMS: Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance. METHODS: Human intestinal biopsy tissues were obtained from patients with COVID-19 (n = 19) and uninfected control individuals (n = 10) for microscopic examination, cytometry by time of flight analyses, and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in 2 large, independent cohorts of hospitalized patients in the United States (N = 634) and Europe (N = 287) using multivariate logistic regressions. RESULTS: COVID-19 case patients and control individuals in the biopsy cohort were comparable for age, sex, rates of hospitalization, and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy in 15 of 17 patients studied. High-dimensional analyses of GI tissues showed low levels of inflammation, including down-regulation of key inflammatory genes including IFNG, CXCL8, CXCL2, and IL1B and reduced frequencies of proinflammatory dendritic cells compared with control individuals. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of sex, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms. CONCLUSIONS: These data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in patients with COVID-19 presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2-associated inflammation needs to be further examined.
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COVID-19/virologia , Gastroenteropatias/virologia , Imunidade nas Mucosas , Mucosa Intestinal/virologia , SARS-CoV-2/patogenicidade , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/mortalidade , Estudos de Casos e Controles , Células Cultivadas , Citocinas/sangue , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/imunologia , Gastroenteropatias/mortalidade , Interações Hospedeiro-Patógeno , Humanos , Mediadores da Inflamação/sangue , Mucosa Intestinal/imunologia , Itália , Masculino , Pessoa de Meia-Idade , Cidade de Nova Iorque , Prognóstico , Medição de Risco , Fatores de Risco , SARS-CoV-2/imunologia , Carga ViralRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with the development of variable levels of antibodies with neutralizing activity, which can protect against infection in animal models1,2. Antibody levels decrease with time, but, to our knowledge, the nature and quality of the memory B cells that would be required to produce antibodies upon reinfection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection with SARS-CoV-2. We find that titres of IgM and IgG antibodies against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 decrease significantly over this time period, with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by fivefold in pseudotype virus assays. By contrast, the number of RBD-specific memory B cells remains unchanged at 6.2 months after infection. Memory B cells display clonal turnover after 6.2 months, and the antibodies that they express have greater somatic hypermutation, resistance to RBD mutations and increased potency, indicative of continued evolution of the humoral response. Immunofluorescence and PCR analyses of intestinal biopsies obtained from asymptomatic individuals at 4 months after the onset of coronavirus disease 2019 (COVID-19) revealed the persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 individuals. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.
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Anticorpos Antivirais/imunologia , COVID-19/imunologia , Imunidade Humoral/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/genética , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/genética , Antígenos Virais/química , Antígenos Virais/genética , Antígenos Virais/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Biópsia , COVID-19/sangue , Estudos de Coortes , Imunofluorescência , Humanos , Imunidade Humoral/genética , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Memória Imunológica/imunologia , Intestinos/imunologia , Pessoa de Meia-Idade , Mutação , Hipermutação Somática de Imunoglobulina , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND AND AIMS: The presence of gastrointestinal symptoms and high levels of viral RNA in the stool suggest active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication within enterocytes. METHODS: Here, in multiple, large cohorts of patients with inflammatory bowel disease (IBD), we have studied the intersections between Coronavirus Disease 2019 (COVID-19), intestinal inflammation, and IBD treatment. RESULTS: A striking expression of ACE2 on the small bowel enterocyte brush border supports intestinal infectivity by SARS-CoV-2. Commonly used IBD medications, both biologic and nonbiologic, do not significantly impact ACE2 and TMPRSS2 receptor expression in the uninflamed intestines. In addition, we have defined molecular responses to COVID-19 infection that are also enriched in IBD, pointing to shared molecular networks between COVID-19 and IBD. CONCLUSIONS: These data generate a novel appreciation of the confluence of COVID-19- and IBD-associated inflammation and provide mechanistic insights supporting further investigation of specific IBD drugs in the treatment of COVID-19. Preprint doi: https://doi.org/10.1101/2020.05.21.109124.
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Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/enzimologia , Doenças Inflamatórias Intestinais/enzimologia , Mucosa Intestinal/enzimologia , SARS-CoV-2/patogenicidade , Serina Endopeptidases/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Animais , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , COVID-19/genética , COVID-19/virologia , Estudos de Casos e Controles , Ensaios Clínicos como Assunto , Estudos Transversais , Modelos Animais de Doenças , Feminino , Redes Reguladoras de Genes , Interações Hospedeiro-Patógeno , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/virologia , Estudos Longitudinais , Masculino , Camundongos , SARS-CoV-2/efeitos dos fármacos , Serina Endopeptidases/genética , Transdução de Sinais , Tratamento Farmacológico da COVID-19RESUMO
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with development of variable levels of antibodies with neutralizing activity that can protect against infection in animal models. Antibody levels decrease with time, but the nature and quality of the memory B cells that would be called upon to produce antibodies upon re-infection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection. We find that IgM, and IgG anti-SARS-CoV-2 spike protein receptor binding domain (RBD) antibody titers decrease significantly with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by five-fold in pseudotype virus assays. In contrast, the number of RBD-specific memory B cells is unchanged. Memory B cells display clonal turnover after 6.2 months, and the antibodies they express have greater somatic hypermutation, increased potency and resistance to RBD mutations, indicative of continued evolution of the humoral response. Analysis of intestinal biopsies obtained from asymptomatic individuals 4 months after coronavirus disease-2019 (COVID-19) onset, using immunofluorescence, or polymerase chain reaction, revealed persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 volunteers. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.
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Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of coronavirus disease 2019 (COVID-19), we investigated intestinal infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its effect on disease pathogenesis. SARS-CoV-2 was detected in small intestinal enterocytes by immunofluorescence staining or electron microscopy, in 13 of 15 patients studied. High dimensional analyses of GI tissues revealed low levels of inflammation in general, including active downregulation of key inflammatory genes such as IFNG, CXCL8, CXCL2 and IL1B and reduced frequencies of proinflammatory dendritic cell subsets. To evaluate the clinical significance of these findings, examination of two large, independent cohorts of hospitalized patients in the United States and Europe revealed a significant reduction in disease severity and mortality that was independent of gender, age, and examined co-morbid illnesses. The observed mortality reduction in COVID-19 patients with GI symptoms was associated with reduced levels of key inflammatory proteins including IL-6, CXCL8, IL-17A and CCL28 in circulation but was not associated with significant differences in nasopharyngeal viral loads. These data draw attention to organ-level heterogeneity in disease pathogenesis and highlight the role of the GI tract in attenuating SARS-CoV-2-associated inflammation with related mortality benefit. ONE SENTENCE SUMMARY: Intestinal infection with SARS-CoV-2 is associated with a mild inflammatory response and improved clinical outcomes.
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We sought to characterize the role of the gastrointestinal immune system in the pathogenesis of the inflammatory response associated with COVID-19. We measured cytokines, inflammatory markers, viral RNA, microbiome composition and antibody responses in stool from a cohort of 44 hospitalized COVID-19 patients. SARS-CoV-2 RNA was detected in stool of 41% of patients and more frequently in patients with diarrhea. Patients who survived had lower fecal viral RNA than those who died. Strains isolated from stool and nasopharynx of an individual were the same. Compared to uninfected controls, COVID-19 patients had higher fecal levels of IL-8 and lower levels of fecal IL-10. Stool IL-23 was higher in patients with more severe COVID-19 disease, and we found evidence of intestinal virus-specific IgA responses associated with more severe disease. We provide evidence for an ongoing humeral immune response to SARS-CoV-2 in the gastrointestinal tract, but little evidence of overt inflammation.
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In the preceding article, we present a flexibility analysis of the voltage-gated ion channel (VGIC) superfamily. In this study, we describe in detail the flexibility profile of the voltage-sensor domain (VSD) and the pore domain (PD) concerning the evolution of 6TM ion channels. In particular, we highlight the role of flexibility in the emergence of CNG channels and describe a significant level of sequence similarity between the archetypical VSD and the TolQ proteins. A highly flexible S4-like segment exhibiting Lys instead Arg for these membrane proteins is reported. Sequence analysis indicates that, in addition to this S4-like segment, TolQ proteins also show similarity with specific motifs in S2 and S3 from typical V-sensors. Notably, S3 flexibility profiles from typical VSDs and S3-like in TolQ proteins are also similar. Interestingly, TolQ from early divergent prokaryotes are comparatively more flexible than those in modern counterparts or true V-sensors. Regarding the PD, we also found that 2TM K+-channels in early prokaryotes are considerably more flexible than the ones in modern microbes, and such flexibility is comparable to the one present in CNG channels. Voltage dependence is mainly exhibited in prokaryotic CNG channels whose VSD is rigid whereas the eukaryotic CNG channels are considerably more flexible and poorly V-dependent. The implication of the flexibility present in CNG channels, their sensitivity to cyclic nucleotides and the cation selectivity are discussed. Finally, we generated a structural model of the putative cyclic nucleotide-modulated ion channel, which we coined here as AqK, from the thermophilic bacteria Aquifex aeolicus, one of the earliest diverging prokaryotes known. Overall, our analysis suggests that V-sensors in CNG-like channels were essentially rigid in early prokaryotes but raises the possibility that this module was probably part of a very flexible stator protein of the bacterial flagellum motor complex.
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Bactérias/metabolismo , Proteínas de Bactérias/química , Canais de Cátion Regulados por Nucleotídeos Cíclicos/química , Motivos de Aminoácidos , Sequência de Aminoácidos , Aquifex , Bactérias/química , Bactérias/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/metabolismo , Evolução Molecular , Ligantes , Família Multigênica , Nucleotídeos Cíclicos/química , Nucleotídeos Cíclicos/metabolismo , Domínios Proteicos , Alinhamento de SequênciaRESUMO
Cellular mRNAs cycle between translating and non-translating pools, polysomes compose the translating pool, while RNA granules contain translationally-silenced mRNAs, where the RNAs are either stored in stress granules, or accumulate in processing bodies (PBs) or GW-bodies, which have an important role in RNA degradation. Viruses have developed measures to prevent the deleterious effects of these structures during their replication. Rotavirus, the most common agent of viral gastroenteritis, is capable of establishing a successful infection by counteracting several of the antiviral responses of its host. Here, we describe that in rotavirus-infected cells the distribution of several RNA binding proteins is changed causing the disaggregation of PBs, the relocalization of GW-body proteins, and the cytoplasmic accumulation of HuR, a predominantly nuclear protein. We show that this redistribution of proteins is more likely caused by the accumulation of viral RNA in the cytoplasm of infected-cells, where it might be acting as an RBP sponge.
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Transporte Proteico/fisiologia , RNA Viral/fisiologia , Proteínas de Ligação a RNA/fisiologia , Rotavirus/genética , Animais , Anticorpos Antivirais , Linhagem Celular , Regulação da Expressão Gênica , Macaca mulatta , RNA Mensageiro/química , RNA Mensageiro/fisiologia , Proteínas de Ligação a RNA/química , Rotavirus/fisiologiaRESUMO
Extensive research is currently underway, seeking better diagnostic methods and treatments and a better understanding of the molecular mechanisms involved in cancer, from the role of specific genetic mutations to the intricate biochemical and molecular pathways involved. Because of their role in regulating relevant physiological events such as cell proliferation, migration, and invasion, ion channels have recently been recognized as important elements in cancer initiation and progression. Moreover, it has been reported that pharmacological intervention in ion channel activity might provide protection against diverse types of cancer, and that ion channels could be used as targets to counteract tumor growth, prevent metastasis, and overcome the therapy resistance of tumor cells. In this context, Ca2+ channels have been found to play a role in tumorigenesis and tumor progression. Specifically, L-type Ca2+ channel inhibition may affect cell proliferation, differentiation, and apoptosis. This review aims to provide insights into the potential role of these channels in cancer cell lines, emphasizing their participation in cell proliferation, migration, and autophagy induction, as well as their potential as rational targets for new cancer therapeutics.
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Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio , Movimento Celular , Proliferação de Células , Neoplasias/genética , Neoplasias/patologia , Autofagia , Canais de Cálcio Tipo L/genética , Sinalização do Cálcio/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológicoRESUMO
Gamma-aminobutyric acid (GABA)ρ receptors are selectively targeted to the axon terminals of the retinal bipolar neurons. The traffic of a green fluorescent protein-tagged GABAρ2 was examined in retinal bipolar neurons and cerebellar astrocytes. In bipolar neurons, time-lapse laser confocal microscopy revealed that the fluorescence emitted by GABAρ2-green fluorescent protein accumulates first, in clusters, in the soma and is then distributed along the axon in at least two populations: one that remains relatively immobile and a second population of smaller clusters that moved constantly to and from the axon end. In astrocytes, the fluorescent clusters were relatively immobile and located mainly in the soma.
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Astrócitos/metabolismo , Receptores de GABA/metabolismo , Células Bipolares da Retina/metabolismo , Animais , Axônios/metabolismo , Cerebelo/metabolismo , Microscopia Confocal , Transporte Proteico , Ratos , Ratos WistarRESUMO
RIG-I (retinoic acid-inducible gene I) and TRIM25 (tripartite motif protein 25) have emerged as key regulatory factors to induce interferon (IFN)-mediated innate immune responses to limit viral replication. Upon recognition of viral RNA, TRIM25 E3 ligase binds the first caspase recruitment domain (CARD) of RIG-I and subsequently induces lysine 172 ubiquitination of the second CARD of RIG-I, which is essential for the interaction with downstream MAVS/IPS-1/CARDIF/VISA and, thereby, IFN-beta mRNA production. Although ubiquitination has emerged as a major factor involved in RIG-I activation, the potential contribution of other post-translational modifications, such as phosphorylation, to the regulation of RIG-I activity has not been addressed. Here, we report the identification of serine 8 phosphorylation at the first CARD of RIG-I as a negative regulatory mechanism of RIG-I-mediated IFN-beta production. Immunoblot analysis with a phosphospecific antibody showed that RIG-I serine 8 phosphorylation steady-state levels were decreased upon stimulation of cells with IFN-beta or virus infection. Substitution of serine 8 in the CARD RIG-I functional domain with phosphomimetic aspartate or glutamate results in decreased TRIM25 binding, RIG-I ubiquitination, MAVS binding, and downstream signaling. Finally, sequence comparison reveals that only primate species carry serine 8, whereas other animal species carry an asparagine, indicating that serine 8 phosphorylation may represent a primate-specific regulation of RIG-I activation. Collectively, these data suggest that the phosphorylation of RIG-I serine 8 operates as a negative switch of RIG-I activation by suppressing TRIM25 interaction, further underscoring the importance of RIG-I and TRIM25 connection in type I IFN signal transduction.
Assuntos
RNA Helicases DEAD-box/metabolismo , Interferon beta/metabolismo , Serina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação/genética , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Proteína DEAD-box 58 , RNA Helicases DEAD-box/química , RNA Helicases DEAD-box/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/genética , Interferon beta/farmacologia , Microscopia Confocal , Modelos Moleculares , Mutação , Fosforilação/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ligação Proteica , Estrutura Terciária de Proteína , Receptores Imunológicos , Serina/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional , Transfecção , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Células VeroRESUMO
The present review discusses the functional and molecular diversity of GABAρ receptors. These receptors were originally described in the mammalian retina, and their functional role in the visual pathway has been recently elucidated; however new studies on their distribution in the brain and spinal cord have revealed that they are more spread than originally thought, and thus it will be important to determine their physiological contribution to the GABAergic transmission in other areas of the central nervous system. In addition, molecular modeling has revealed peculiar traits of these receptors that have impacted on the interpretations of the latest pharmacolgical and biophysical findings. Finally, sequencing of several vertebrate genomes has permitted a comparative analysis of the organization of the GABAρ genes.