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1.
J Biol Chem ; 298(12): 102685, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36370845

RESUMO

Brain-specific angiogenesis inhibitor 1 (BAI1; also called ADGRB1 or B1) is an adhesion G protein-coupled receptor known from studies on macrophages to bind to phosphatidylserine (PS) on apoptotic cells via its N-terminal thrombospondin repeats. A separate body of work has shown that B1 regulates postsynaptic function and dendritic spine morphology via signaling pathways involving Rac and Rho. However, it is unknown if PS binding by B1 has any effect on the receptor's signaling activity. To shed light on this subject, we studied G protein-dependent signaling by B1 in the absence and presence of coexpression with the PS flippase ATP11A in human embryonic kidney 293T cells. ATP11A expression reduced the amount of PS exposed extracellularly and also strikingly reduced the signaling activity of coexpressed full-length B1 but not a truncated version of the receptor lacking the thrombospondin repeats. Further experiments with an inactive mutant of ATP11A showed that the PS flippase function of ATP11A was required for modulation of B1 signaling. In coimmunoprecipitation experiments, we made the surprising finding that ATP11A not only modulates B1 signaling but also forms complexes with B1. Parallel studies in which PS in the outer leaflet was reduced by an independent method, deletion of the gene encoding the endogenous lipid scramblase anoctamin 6 (ANO6), revealed that this manipulation also markedly reduced B1 signaling. These findings demonstrate that B1 signaling is modulated by PS exposure and suggest a model in which B1 serves as a PS sensor at synapses and in other cellular contexts.


Assuntos
Fosfatidilserinas , Transdução de Sinais , Humanos , Fosfatidilserinas/genética , Fosfatidilserinas/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/genética , Trombospondinas/metabolismo , Células HEK293
2.
Physiol Rev ; 102(4): 1587-1624, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35468004

RESUMO

Adhesion G protein-coupled receptors (AGPCRs) are a family of 33 receptors in humans exhibiting a conserved general structure but diverse expression patterns and physiological functions. The large NH2 termini characteristic of AGPCRs confer unique properties to each receptor and possess a variety of distinct domains that can bind to a diverse array of extracellular proteins and components of the extracellular matrix. The traditional view of AGPCRs, as implied by their name, is that their core function is the mediation of adhesion. In recent years, though, many surprising advances have been made regarding AGPCR signaling mechanisms, activation by mechanosensory forces, and stimulation by small-molecule ligands such as steroid hormones and bioactive lipids. Thus, a new view of AGPCRs has begun to emerge in which these receptors are seen as massive signaling platforms that are crucial for the integration of adhesive, mechanosensory, and chemical stimuli. This review article describes the recent advances that have led to this new understanding of AGPCR function and also discusses new insights into the physiological actions of these receptors as well as their roles in human disease.


Assuntos
Receptores Acoplados a Proteínas G , Transdução de Sinais , Adesão Celular , Humanos , Ligantes , Receptores Acoplados a Proteínas G/metabolismo
3.
Exp Neurol ; 351: 113994, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35114205

RESUMO

The adhesion G protein-coupled receptor BAI1/ADGRB1 plays an important role in suppressing angiogenesis, mediating phagocytosis, and acting as a brain tumor suppressor. BAI1 is also a critical regulator of dendritic spine and excitatory synapse development and interacts with several autism-relevant proteins. However, little is known about the relationship between altered BAI1 function and clinically relevant phenotypes. Therefore, we studied the effect of reduced expression of full length Bai1 on behavior, seizure susceptibility, and brain morphology in Adgrb1 mutant mice. We compared homozygous (Adgrb1-/-), heterozygous (Adgrb1+/-), and wild-type (WT) littermates using a battery of tests to assess social behavior, anxiety, repetitive behavior, locomotor function, and seizure susceptibility. We found that Adgrb1-/- mice showed significant social behavior deficits and increased vulnerability to seizures. Adgrb1-/- mice also showed delayed growth and reduced brain weight. Furthermore, reduced neuron density and increased apoptosis during brain development were observed in the hippocampus of Adgrb1-/- mice, while levels of astrogliosis and microgliosis were comparable to WT littermates. These results show that reduced levels of full length Bai1 is associated with a broader range of clinically relevant phenotypes than previously reported.


Assuntos
Proteínas Angiogênicas/metabolismo , Receptores Acoplados a Proteínas G , Proteínas Angiogênicas/genética , Animais , Encéfalo/metabolismo , Hipocampo/metabolismo , Camundongos , Receptores Acoplados a Proteínas G/genética , Convulsões/genética , Convulsões/metabolismo
4.
Exp Neurol ; 342: 113719, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33839144

RESUMO

The generation of neural stem and progenitor cells following injury is critical for the function of the central nervous system, but the molecular mechanisms modulating this response remain largely unknown. We have previously identified the G protein-coupled receptor 37 (GPR37) as a modulator of ischemic damage in a mouse model of stroke. Here we demonstrate that GPR37 functions as a critical negative regulator of progenitor cell dynamics and gliosis following ischemic injury. In the central nervous system, GPR37 is enriched in mature oligodendrocytes, but following injury we have found that its expression is dramatically increased within a population of Sox2-positive progenitor cells. Moreover, the genetic deletion of GPR37 did not alter the number of mature oligodendrocytes following injury but did markedly increase the number of both progenitor cells and injury-induced Olig2-expressing glia. Alterations in the glial environment were further evidenced by the decreased activation of oligodendrocyte precursor cells. These data reveal that GPR37 regulates the response of progenitor cells to ischemic injury and provides new perspectives into the potential for manipulating endogenous progenitor cells following stroke.


Assuntos
Isquemia Encefálica/metabolismo , Modelos Animais de Doenças , AVC Isquêmico/metabolismo , Receptores Acoplados a Proteínas G/deficiência , Células-Tronco/metabolismo , Animais , Isquemia Encefálica/patologia , Isquemia Encefálica/prevenção & controle , AVC Isquêmico/patologia , AVC Isquêmico/prevenção & controle , Masculino , Camundongos , Camundongos Knockout , Receptores Acoplados a Proteínas G/biossíntese , Receptores Acoplados a Proteínas G/genética , Células-Tronco/patologia
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