RGS2

G蛋白偶联受体（GPCR）是最大的跨膜蛋白家族，其作用是将细胞外刺激转化为细胞内信号反应。人们发现G蛋白信号传导（RGS）表达或功能的紊乱可能导致多种心脏代谢疾病的发病机制。 G蛋白偶联受体（GPCR）是最大的跨膜蛋白家族，其作用是将细胞外刺激转化为细胞内信号反应。人们发现G蛋白信号传导（RGS）表达或功能的紊乱可能导致多种心脏代谢疾病的发病机制。在许多心脏代谢状况中观察到GPCR信号传导失调。 这种失调并不总是直接归因于受体本身，而是归因于GPCR介导的途径（包括换能器、调节器和效应器）的关键成分的活性和/或表达的改变。在人类患者和动物模型中，Gi/o表达增强与心力衰竭有关。其他GPCR调节因子也与心脏代谢疾病表型有关。这可能有助于了解心脏代谢疾病的发病机制。 图片来源：https://pubmed.ncbi.nlm.nih.gov/36964984/ 近日，来自蒙纳士大学的研究者们在Br J Pharmacol.杂志上发表了题为“The roles of RGS proteins in cardiometabolic disease”的文章，该综述总结了RGS蛋白在心脏代谢功能中的作用，重点介绍了它们在各种疾病条件下的组织分布、作用机制和失调。 G蛋白偶联受体（GPCR）是细胞表面最突出的受体，在心脏和代谢功能的调节中发挥着核心作用。GPCR通过激活一种或多种异源三聚体G蛋白将细胞外刺激传递到细胞内部。RGS蛋白在心血管系统中具有重要的调节作用。 早期证据表明，在体外细胞模型中共表达RGS蛋白可以再现在天然心脏组织中观察到的GIRK通道的快速失活动力学。由于GIRK通道电流是维持正常心率的核心，因此在动物模型和人类中，RGS蛋白的差异表达或RGS功能受损与高血压和低血压表型有关并不奇怪。 与RGS介导的M2受体/Gi/o信号传导的负调控相反，RGS2选择性地减弱血管系统中的Gq信号传导以影响心脏功能。缺乏RGS2的小鼠表现出强烈的高血压表型，其特征是血管张力增加和对GPCR（的延长信号传导的依赖，从而导致有效的小动脉血管收缩。 尽管如此，另一项研究报告称，RGS2 KO小鼠对NO供体硝普钠的反应显示出血管舒张减少，这表明RGS2介导的血压调节的另一种机制。这些发现可能具有临床相关性，因为在从Bartter's/Gitelman综合征患者分离的外周血单核细胞中观察到RGS2过表达。 尽管血浆血管紧张素II水平升高，但这种情况与正常血压/低血压和血管紧张素Ⅱ介导的信号传导降低有关。相反，与血压正常的对照受试者相比，高血压患者在分离的外周血单核细胞中RGS2的表达显著降低。此外，RGS2基因内的单核苷酸多态性与人类高血压密切相关，这表明RGS2是血管张力的潜在关键调节因子。 RGS蛋白在心脏病理生理学中的作用。 图片来源：https://pubmed.ncbi.nlm.nih.gov/36964984/ 综上所述，除了靶向途径和控制RGS蛋白稳定性的关键调节因子，还可通过各种基因递送方法直接递送RGS蛋白也可以作为恢复或增强RGS活性的新方法。使用AAV递送RGS蛋白仍然是一个令人兴奋的探索途径，特别是在RGS功能或表达受损的一些心脏代谢疾病的情况下。（生物谷 Bioon.com） 参考文献 Samantha M McNeill et al. The roles of RGS proteins in cardiometabolic disease. Br J Pharmacol. 2023 Mar 25. doi: 10.1111/bph.16076.

Previous analyses within the nucleus accumbens showed that different genes were turned on or off in women, but not in men diagnosed with depression. These changes could have caused symptoms of depression, or alternatively, the experience of being depressed could have changed the brain -- a clue to why anti-depressants had not been successful for some women. Although treatments for depression exist, sometimes these treatments don't work for many who use them. Furthermore, women experience higher rates of depression than men, yet the cause for this difference is unknown, making their illnesses, at times, more complicated to treat. University of California, Davis, researchers teamed up with scientists from Mt. Sinai Hospital, Princeton University, and Laval University, Quebec, to try to understand how a specific part of the brain, the nucleus accumbens, is affected during depression. The nucleus accumbens is important for motivation, response to rewarding experiences and social interactions -- all of which are affected by depression. Previous analyses within the nucleus accumbens showed that different genes were turned on or off in women, but not in men diagnosed with depression. These changes could have caused symptoms of depression, or alternatively, the experience of being depressed could have changed the brain. To differentiate between these possibilities, the researchers studied mice that had experienced negative social interactions, which induce stronger depression-related behavior in females than males. "These high-throughput analyses are very informative for understanding long-lasting effects of stress on the brain. In our rodent model, negative social interactions changed gene expression patterns in female mice that mirrored patterns observed in women with depression," said Alexia Williams, a doctoral researcher and recent UC Davis graduate who designed and led these studies. "This is exciting because women are understudied in this field, and this finding allowed me to focus my attention on the relevance of these data for women's health." The study "Comparative transcriptional analyses in the nucleus accumbens identifies RGS2 as a key mediator of depression-related behavior," was published this month in the journal Biological Psychiatry. After identifying similar molecular changes in the brains of mice and humans, researchers chose one gene, regulator of g protein signaling-2, or Rgs2, to manipulate. This gene controls the expression of a protein that regulates neurotransmitter receptors that are targeted by antidepressant medications such as Prozac and Zoloft. "In humans, less stable versions of the Rgs2 protein are associated with increased risk of depression, so we were curious to see whether increasing Rgs2 in the nucleus accumbens could reduce depression-related behaviors," said Brian Trainor, UC Davis professor of psychology and senior author on the study. He is also an affiliated faculty member with the Center for Neuroscience and directs the Behavioral Neuroendocrinology Lab at UC Davis. When the researchers experimentally increased Rgs2 protein in the nucleus accumbens of the mice, they effectively reversed the effects of stress on these female mice, noting that social approach and preferences for preferred foods increased to levels observed in females that did not experience any stress. "These results highlight a molecular mechanism contributing to the lack of motivation often observed in depressed patients. Reduced function of proteins like Rgs2 may contribute to symptoms that are difficult to treat in those struggling with mental illnesses," Williams said. Findings from basic science studies such as this one may guide the development of pharmacotherapies to effectively treat individuals suffering from depression, the researchers said. "Our hope is that by doing studies such as these, which focus on elucidating mechanisms of specific symptoms of complex mental illnesses, we will bring science one step closer to developing new treatments for those in need," said Williams. In addition to Trainor and Williams, co-authors include, from Princeton University, Catherine Peña; from Icahn School of Medicine at Mount Sinai, Randal Serafini, Anne Ruiz, Venetia Zachariou and Eric Nestler; from Laval University, Benoit Labonte; from Massachusetts General Hospital, Rachel Neve; and Stephanie Ramos-Maciel, Abigail Laman-Maharg, Evelyn Ordoñez-Sanchez, Monica Britton, Blyther Durbin-Johnson, Matt Settles, Rebecca Hao, Sae Yokoyama, Christine Xu, Pei Luo, Tjien Dwyer, Shanu Bhela and Alexis Black, all UC Davis researchers.