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Straightening out serotonin receptors
by Kelsey Kaustinen  |  Email the author


LA JOLLA, Calif.ŚSerotonin is one of the best- known chemicals in the human brain, mainly due to its role in the reward center. But now some of serotonin's receptors are getting some attention as well, thanks to new findings on how certain serotonin receptors interact with and affect some drugs.  
This work was conducted by a team of researchers from The Scripps Research Institute (TSRI), the University of North Carolina (UNC) at Chapel Hill and the Chinese Academy of Sciences, and focused on the analysis of high-resolution atomic structures of two kinds of human serotonin receptors.  
The laboratory of TSRI Prof. Raymond Stevens, a senior investigator for the new research, pioneered the development of techniques for the determination of the 3D atomic structures of cellular receptors, particularly those that fall into the class of G protein-coupled receptors (GPCRs). The Stevens laboratory has used X-ray crystallography to determine the structures of 10 of the most important GPCRs in the human body, including the ▀2 adrenergic receptor, the A2a adenosine receptor, HIV-related CXCR4 receptor, the nociceptin receptor, S1P1 receptor, H1 histamine receptor and the D3 domapine receptor. These receptors affect issues such as pain mediation, inflammatory disease, antihistamine medications and mood.  
"Because G protein-coupled receptors are the targets of nearly 50 percent of medicines, they are the focus of several major National Institutes of Health (NIH) initiatives," Jean Chin of the NIH's National Institute of General Medical Sciences (NIGMS) said in a press release. The NIGMS partly funded this work through the Protein Structure Initiative. "These detailed molecular structures of two serotonin receptor subfamilies bound to antimigraines, antipsychotics, antidepressants or appetite suppressants will help us understand how normal cellular signaling is affect by these drugs, and will offer a valuable framework for designing safer and more effective medicines."  
Serotonin, for its part, is linked not only to mood regulation and the brain's reward center, but also to consciousness and the body's sleep/wake cycles, according to Daniel Wacker, lead author and TSRI graduate student.
  Bryan Roth, a professor of pharmacology at UNC and a collaborator on both studies, noted in a press release that serotonin receptors "also mediate a host of effects outside the brain, for example on blood coagulation, smooth muscle contraction and heart valve growth."
In the first study, Chong Wang, co-lead author and a graduate student in the Stevens lab, and colleagues determined the atomic structure of serotonin receptor subtype 5-HT1B, and produced the receptor while it was bound with either ergotamine or dihydroergotamine, anti-migraine drugs that activate 5-HT1B receptors. A special fusion protein known as BRIL was used to stabilize the structures and line them up in a regular crystal ordering. When x-ray crystallography was applied, it revealed the atomic structure of the receptor with a main binding pocket as well as a separate, extended binding pocket.  
Wacker and colleagues took a similar approach in the second study in determining the structure of the 5-HT2B receptor bound to ergotamine. The 5-HT2B receptor is a target most drug developers want to avoid due to the off-target, and usually harmful, effects that can result. In 1997, fenfluramine and dexfenfluramine, two weight- loss drugs, were pulled from the U.S. market after being linked to heart valve disease, which Roth's lab later discovered was thanks to heart valve 5 -HT2B receptors. Wacker says they were "absolutely not" expecting the results their studies presented.  
"We knew that particular drugs hit both receptors, but we had no idea how similar their interactions were, because if you were to model the receptors based on other structures, you would have never gotten to the results we've gotten," he explains. "I think the biggest surprise for us was that the same compound binds in a very similar manner to two different receptors, but the receptors, in key areas of their structure, are very different. So exploiting these particular areas and improving the drugs will hopefully lead to making safer and more selective medications. "
The labs of Profs. Eric Xu and Hualiang Jiang at the Shanghai Institute of Materia Medica, part of the Chinese Academy of Sciences, then used the receptor structures to simulate the bindings of various drugs, demonstrating that anti-migraine drugs, known as triptans, should bind well to the 5-HT1B receptors, but poorly to 5-HT2B receptors, while fenfluramine's active metabolite ought to bind tightly with the 5-HT2B receptor. Roth's lab found that ergotamine and LSD, an ergotamine-derived hallucinogen, favor ▀-arrestin signaling at the 5-HT2B receptor.
"I think the big breakthrough of this, the big insight from these studies, comes from providing selectivity information," says Wacker. "A lot of drugs that were designed to target specific serotonin receptors were found to also target the serotonin receptor 5-HT2B. It was later found that activation of this receptor causes valvular heart disease and pulmonary hypertension. So looking at these structures and figuring out a way of how to avoid binding and activation the 5-HT2B receptor, or even to find drugs that would antagonize it, would be very beneficial."  
The two ways to avoid triggering the 5-HT2B receptor, Wacker notes, would be to either modify a drug so that it is incapable of binding with the receptor, or to assign an antagonist for the receptor. Moving forward, he adds that looking at more of the serotonergic receptor class is important, as a close relative of the 5-HT2B receptors, the 5HT-2C receptor, is a good target for appetite-suppressing anti-obesity drugs. The knowledge of both structures, he says, could allow for safer medications that would avoid fenfluramine and dexfenfluramine's harmful side effects.  
The two studies are titled "Structural Basis for Molecular Recognition at Serotonin Receptors" and "Structural Features for Functional Selectivity at Serotonin Receptors," and appeared in two papers on March 21 in Science Express, the advance online version of Science.  

Code: E04101304



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