Maybe we dont have enough Shisa7...

Abstract

The function and pharmacology of γ-aminobutyric acid type A receptors (GABAARs) are of great physiological and clinical importance and have long been thought to be determined by the channel pore-forming subunits. We discovered that Shisa7, a single-passing transmembrane protein, localizes at GABAergic inhibitory synapses and interacts with GABAARs. Shisa7 controls receptor abundance at synapses and speeds up the channel deactivation kinetics. Shisa7 also potently enhances the action of diazepam, a classic benzodiazepine, on GABAARs. Genetic deletion of Shisa7 selectively impairs GABAergic transmission and diminishes the effects of diazepam in mice. Our data indicate that Shisa7 regulates GABAAR trafficking, function, and pharmacology and reveal a previously unknown molecular interaction that modulates benzodiazepine action in the brain.

any thoughts?

There was a guy on here named cs123. He always did a tremendous amount of research. He hasn't been on here for a couple of days. He's very knowledgeable.

Interesting topic!

"Further experiments suggested that Shisa7 proteins attached directly to GABAA receptors. Electrical recordings showed that Shisa7 hastened receptor responses to the transmitter GABA and nearly doubled the size of responses made in the presence of Valium (a.k.a. diazepam), suggesting the protein made the receptor more sensitive to benzodiazepines.

“These results suggest that Shisa7 directly shapes inhibitory synaptic responses under a variety of conditions, including the presence of benzodiazepines,” said Dr. McBain.

Finally, experiments in mice supported the idea that Shisa7 also plays a role in the calming effects of benzodiazepines. For instance, in one set, they tested the ability of diazepam to reduce the high anxiety mice felt when confronted with open, elevated spaces.

Here, the mice were placed in the middle of an elevated maze of two crisscrossing arms. One arm was covered and the other open. In agreement with previous studies, the researchers saw that injections of diazepam increased the time the wild-type mice chose to walk on open arms, suggesting the drug reduced anxiety. In contrast, diazepam had no effect on mice that were engineered to have no Shisa7 gene. These mice spent the same amount of time exploring the open arms regardless of whether they received the drug or a placebo.

In other experiments, the researchers found that Shisa7 also influenced the drowsiness and hypnotic effects of benzodiazepines. Mice that lacked Shisa7 were much less likely than wild-type mice to fall asleep from high levels of diazepam. Moreover, the mutant mice were dramatically better at standing up after diazepam-induced stumbles, in fact, some appeared resistant to stumbling.

“Our results shine a spotlight on the potential clinical importance of auxiliary proteins like Shisa7. Many of the neurological drugs we use today are designed to control the activity of synaptic receptors. For the first time, we show that researchers may also want to consider auxiliary proteins like Shisa7 in developing new treatments that target GABAA receptors,” said Dr."