RESUMEN
The ubiquitin ligase, Ube3a, plays important roles in brain development and functions, since its deficiency results in Angelman Syndrome (AS) while its over-expression increases the risk for autism. We previously showed that the lack of Ube3a-mediated ubiquitination of the Ca2+-activated small conductance potassium channel, SK2, contributes to impairment of synaptic plasticity and learning in AS mice. Synaptic SK2 levels are also regulated by protein kinase A (PKA), which phosphorylates SK2 in its C-terminal domain, facilitating its endocytosis. Here, we report that PKA activation restores theta burst stimulation (TBS)-induced long-term potentiation (LTP) in hippocampal slices from AS mice by enhancing SK2 internalization. While TBS-induced SK2 endocytosis is facilitated by PKA activation, SK2 recycling to synaptic membranes after TBS is inhibited by Ube3a. Molecular and cellular studies confirmed that phosphorylation of SK2 in the C-terminal domain increases its ubiquitination and endocytosis. Finally, PKA activation increases SK2 phosphorylation and ubiquitination in Ube3a-overexpressing mice. Our results indicate that, although both Ube3a-mediated ubiquitination and PKA-induced phosphorylation reduce synaptic SK2 levels, phosphorylation is mainly involved in TBS-induced endocytosis, while ubiquitination predominantly inhibits SK2 recycling. Understanding the complex interactions between PKA and Ube3a in the regulation of SK2 synaptic levels might provide new platforms for developing treatments for AS and various forms of autism.
Asunto(s)
Síndrome de Angelman/fisiopatología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Hipocampo/patología , Plasticidad Neuronal , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Sinapsis/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Secuencia de Aminoácidos , Síndrome de Angelman/metabolismo , Síndrome de Angelman/patología , Animales , Región CA1 Hipocampal/patología , Región CA1 Hipocampal/fisiopatología , Células COS , Chlorocebus aethiops , Endocitosis , Hipocampo/fisiopatología , Potenciación a Largo Plazo , Ratones , Modelos Moleculares , Mutación , Fosforilación , Dominios Proteicos , Transporte de Proteínas , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/química , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/genética , UbiquitinaciónRESUMEN
Cancer is a condition that has plagued humanity for thousands of years, with the first depictions dating back to ancient Egyptian times. However, not until recent decades have biological therapeutics been developed and refined enough to safely and effectively combat cancer. Three unique immunotherapies have gained traction in recent decades: adoptive T cell transfer, checkpoint inhibitors, and bivalent antibodies. Each has led to clinically approved therapies, as well as to therapies in preclinical and ongoing clinical trials. In this review, we outline the method by which these 3 immunotherapies function as well as any major immunotherapeutic drugs developed for treating a variety of cancers.