Assuntos
Erupções Acneiformes/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Retinoides/administração & dosagem , Erupções Acneiformes/induzido quimicamente , Erupções Acneiformes/imunologia , Administração Oral , Adulto , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias/imunologia , Retinoides/efeitos adversos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Kainate-selective ionotropic glutamate receptors (iGluRs) fulfil key roles in the CNS, making them the subject of detailed structural and functional analyses. Although they are known to gate a channel pore with high and low ion-permeation rates, it is still not clear how switches between these gating modes are achieved at the structural level. Here, we uncover an unexpected role for the ligand-binding domain (LBD) dimer assembly in this process. Covalent crosslinking of the dimer interface keeps kainate receptors out of the main open state but permits access to lower conductance states suggesting that significant rearrangements of the dimer interface are required for the receptor to achieve full activation. These observations differ from NMDA-selective iGluRs where constraining dimer movement reduces open-channel probability. In contrast, our data show that restricting movement of the dimer interface interferes with conformational changes that underlie both activation and desensitization. Working within the limits of a common architectural design, we propose functionally diverse iGluR families were able to emerge during evolution by re-deploying existing gating structures to fulfil different tasks.
Assuntos
Receptores de Ácido Caínico/fisiologia , Linhagem Celular , Ácido Glutâmico/fisiologia , Humanos , Ligantes , Ligação Proteica , Multimerização Proteica , Estrutura Terciária de Proteína , Receptores de Ácido Caínico/química , Receptor de GluK2 CainatoRESUMO
Despite an improved understanding of its pathophysiology and a wide range of new treatments, cardiovascular disease (CVD) remains a serious public health issue and the number one cause of mortality in the United States. Conditions that promote chronic systemic inflammation, such as obesity, cancer, and autoimmune and infectious diseases, are now known to play an important role in promoting CVD by inducing the expression of endothelial adhesion molecules and chemokines; these in turn promote leukocyte adherence and infiltration, which initiates and spurs the progression of CVD. In response to this new understanding, researchers are evaluating the potential cardiovascular benefits of new-generation therapies based on endogenous molecules with anti-inflammatory properties. Similarly, targeted approaches that leverage the phenotypic differences between non-inflamed and inflamed endothelia have the potential to selectively deliver therapeutics and decrease the morbidity and mortality of CVD patients. In this review, we discuss the role of inflammation in CVD and explore the therapeutic potential of targeting inflamed vasculature through conventional and biomimetic approaches.
Assuntos
Fatores Biológicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanomedicina/métodos , Nanopartículas , Vasculite/tratamento farmacológico , HumanosRESUMO
Desensitization is an important mechanism curtailing the activity of ligand-gated ion channels (LGICs). Although the structural basis of desensitization is not fully resolved, it is thought to be governed by physicochemical properties of bound ligands. Here, we show the importance of an allosteric cation-binding pocket in controlling transitions between activated and desensitized states of rat kainate-type (KAR) ionotropic glutamate receptors (iGluRs). Tethering a positive charge to this pocket sustains KAR activation, preventing desensitization, whereas mutations that disrupt cation binding eliminate channel gating. These different outcomes explain the structural distinction between deactivation and desensitization. Deactivation occurs when the ligand unbinds before the cation, whereas desensitization proceeds if a ligand is bound without cation pocket occupancy. This sequence of events is absent from AMPA-type iGluRs; thus, cations are identified as gatekeepers of KAR gating, a role unique among even closely related LGICs.