RESUMO
N-type (CaV2.2) calcium channels are key for action potential-evoked transmitter release in the peripheral and central nervous system. Previous studies have highlighted the functional relevance of N-type calcium channels at both the peripheral and central level. In the periphery, the N-type calcium channels regulate nociceptive and sympathetic responses. At the central level, N-type calcium channels have been linked to aggression, hyperlocomotion, and anxiety. Among the areas of the brain that are involved in anxiety are the basolateral amygdala, medial prefrontal cortex, and ventral hippocampus. These three areas share similar characteristics in their neuronal circuitry, where pyramidal projection neurons are under the inhibitory control of a wide array of interneurons including those that express the peptide cholecystokinin. This type of interneuron is well-known to rely on N-type calcium channels to release GABA in the hippocampus, however, whether these channels control GABA release from cholecystokinin-expressing interneurons in the basolateral amygdala and medial prefrontal cortex is not known. Here, using mouse models to genetically label cholecystokinin-expressing interneurons and electrophysiology, we found that in the basolateral amygdala, N-type calcium channels control ~50% of GABA release from these neurons onto pyramidal cells. By contrast, in the medial prefrontal cortex N-type calcium channels are functionally absent in synapses of cholecystokinin-expressing interneurons, but control ~40% of GABA release from other types of interneurons. Our findings provide insights into the precise localization of N-type calcium channels in interneurons of brain areas related to anxiety.
RESUMO
Aim: Waldenström macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by overproduction of monoclonal IgM. To date, there are no therapies that provide a cure for WM patients, and therefore, it is important to explore new therapies. Little is known about the efficiency of epigenetic targeting in WM. Materials & methods: WM cells were treated with BET inhibitors (JQ1 and I-BET-762) and venetoclax, panobinostat or ibrutinib. Results: BET inhibition reduces growth of WM cells, with little effect on survival. This finding was enhanced by combination therapy, with panobinostat (LBH589) showing the highest synergy. Conclusion: Our studies identify BET inhibitors as effective therapy for WM, and these inhibitors can be enhanced in combination with BCL2 or histone deacetylase inhibition.
Assuntos
Antineoplásicos/farmacologia , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Proteínas do Tecido Nervoso/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptores de Superfície Celular/genética , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adenina/análogos & derivados , Adenina/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Epigênese Genética/genética , Histona Desacetilases/genética , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Terapia de Alvo Molecular/métodos , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Sulfonamidas/farmacologia , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/metabolismoRESUMO
Psychiatric disorders are mental, behavioral or emotional disorders. These conditions are prevalent, one in four adults suffer from any type of psychiatric disorders world-wide. It has always been observed that psychiatric disorders have a genetic component, however, new methods to sequence full genomes of large cohorts have identified with high precision genetic risk loci for these conditions. Psychiatric disorders include, but are not limited to, bipolar disorder, schizophrenia, autism spectrum disorder, anxiety disorders, major depressive disorder, and attention-deficit and hyperactivity disorder. Several risk loci for psychiatric disorders fall within genes that encode for voltage-gated calcium channels (CaVs). Calcium entering through CaVs is crucial for multiple neuronal processes. In this review, we will summarize recent findings that link CaVs and their auxiliary subunits to psychiatric disorders. First, we will provide a general overview of CaVs structure, classification, function, expression and pharmacology. Next, we will summarize tools to study risk loci associated with psychiatric disorders. We will examine functional studies of risk variations in CaV genes when available. Finally, we will review pharmacological evidence of the use of CaV modulators to treat psychiatric disorders. Our review will be of interest for those studying pathophysiological aspects of CaVs.