Science: great progress! It is revealed that gene shisa7 controls the sedative effect of benzodiazepines

October 20, 2019 / Biogen / - - between 1999 and 2017, the number of deaths from overdose of valium and other benzodiazepines in the United States increased tenfold For many years, scientists have believed that these powerful tranquilizers, used to treat anxiety, muscle spasms and sleep disorders, alone play a role in calming nerves Now, in a new study, researchers from the National Institutes of Health (NIH) in the United States have found that this view of the neural circuits of such drugs and their effects may have to change By studying mice, they found that this might require the help of a "sticky" gene named shisa7 The relevant research results were published in the Science Journal on October 11, 2019 The title of the paper is "shisa7 is a GABAA receiver auxiliary subunit controlling benzodiazepine actions" In the study of mice, NIH researchers found that the protein (green) encoded by gene shisa7 may enhance the neurosedative effect of diazepam and other benzodiazepines by attaching to GABAA receptor The picture is from Lu lab, NIH / NINDS "We found that shisa7 plays a key role in the regulation of inhibitory neural circuits and the sedative effect of some benzodiazepines on the activity of neural circuits," said Wei Lu, Ph.D., co-author of the paper and researcher at the National Institutes of Neurology and stroke (NINDS), National Institutes of health We hope that these results will help scientists design more effective treatments for various neurological and neuropsychiatric diseases caused by problems in these circuits " Lu lab has studied genes and molecules that control synapses There are trillions of synapses or communication points between neurons in the whole nervous system In the new study, his team worked with a team led by Chris J McBain, a senior researcher at the National Institutes of health and human development (NICHD), to study synapses that rely on the neurotransmitter GABA to calm the nerves When a neuron releases a large number of GABA molecules, these molecules will soon be detected on the surface of adjacent neurons by a protein called GABA type A (GABAA) receptor, which is the way that different neurons communicate through synapses Prior to this study, benzodiazepines were thought to independently enhance the neurosedative response of GABAA receptors Lu's lab found, on the contrary, that these reactions may largely depend on whether the protein encoded by the shisa7 gene is attached to the GABAA receptor Although these results could eventually help scientists better understand these sedatives, the study began with a simple question about shisa7 In 2004, Japanese researchers first discovered that the shisa gene played a role in the formation of frog heads, and named it after a mythical protective god with a large head depicted in a statue in southern Japan Like many scientists, Lu initially believed that shisa7 played a role in controlling completely different types of synapses - they rely on the neurotransmitter glutamate to activate rather than sedate neurons Recent studies have shown that shisa7 is attached to glutamate receptor with other proteins encoded by shisa gene Once attached, these "helper" proteins control the glutamate receptor's response to glutamate or its presence in the synapse However, a few years ago, Lu's team noticed something interesting in a scientific article about the shisa protein Lu said, "we found amazing results This article suggests that shisa7 is the only protein in this family that seems to have no effect on the activity of important types of glutamate receptors This attracted our attention and we decided to study it carefully " To this end, Dr Wenwen Han, a postdoctoral researcher of NINDS, worked with other researchers in Lu laboratory to systematically study the shisa protein in mouse neurons To their surprise, they found that shisa7 seemed to play a unique and crucial role in the GABA synapse, which calms nerves With the help of scientists from Dr Ling Gang Wu, senior researcher of NINDS, and Dr Ronald s petralia, National Institute of deaf mute and other communication disorders (NIDCD), National Research Institute of the United States, using advanced microscopy, these researchers found that shisa7 was closely clustered on the GABAA receptor on the synaptic surface The elimination of shisa7 from neurons by gene will reduce the number of GABAA receptors and the current intensity of synaptic GABAA receptor response Further experiments showed that shisa7 protein was directly attached to GABAA receptor Electrical recordings showed that shisa7 accelerated the response of GABAA receptor to GABA, a neurotransmitter, and almost doubled the response size in the presence of diazepam, indicating that the protein made the receptor more sensitive to benzodiazepines "These results suggest that shisa7 directly forms inhibitory synapses under a variety of conditions, including the presence of benzodiazepines," said Dr McBain Finally, the experiments in mice support that shisa7 also plays a role in the sedative effect of benzodiazepines For example, in a group of experiments, they tested the ability of diazepam to reduce the high level of anxiety in mice facing open elevated spaces To do this, they placed the mice in the middle of an elevated maze of two crossed arms One arm is covered and the other is open Consistent with previous studies, the researchers found that administration of diazepam to these mice increased the time that wild-type mice chose to walk on open arms, suggesting that the drug reduced anxiety In contrast, diazepam had no effect on mice genetically engineered to lack the shisa7 gene Whether injected with diazepam or placebo, the mice lacking the shisa7 gene spent the same amount of time exploring open arms In other experiments, the researchers found that shisa7 also affects the drowsiness and hypnosis of benzodiazepines Compared with wild-type mice, mice lacking shisa7 were much less likely to fall asleep after high-dose diazepam injection In addition, after the fall caused by diazepam, the ability of mutant mice to stand up was significantly improved In fact, some mutant mice showed resistance to fall "Our results draw attention to the potential clinical importance of helper proteins such as shisa7," Lu said Many of the neurodrugs we currently use are designed to control the activity of synaptic receptors This is the first time we have found that when developing new therapies targeting GABAA receptors, researchers may also want to consider proteins such as shisa7 His team plans to explore in more detail the potential role of shisa7 in inhibitory circuits and other neurological disorders (bio Com) reference: 1 Wenyan Han et al Shisa7 is a GABAA receiver auxiliary subunit controlling benzodiazepine actions Science, 2019, DOI: 10.1126/science.aax5719 2 UWE Rudolph et al Modulating economy and activity Science, 2019, doi:10.1126/science.aaz3176 3.'Sticky' gene may help Valium calm nerves https://medicalxpress.com/news/2019-10-sticky-gene-valium-calm-nerves.html