Serotonin Receptors Can Shape Drug Effects from LSD to Migraine Medication

A team has determined and analyzed the high-resolution atomic structures of two kinds of human serotonin receptor, findings that shed light on several drugs' complex and sometimes harmful effects. 

Credit: Photo courtesy of The Scripps Research Institute.

A team including scientists from The Scripps Research Institute (TSRI), the University of North Carolina at Chapel Hill and the Chinese Academy of Sciences has determined and analyzed the high-resolution atomic structures of two kinds of human serotonin receptor.

The new findings help explain why some drugs that interact with these receptors have had unexpectedly complex and sometimes harmful effects.

"Understanding the structure-function of these receptors allows us to discover new biology of serotonin signaling and also gives us better ideas about what biological questions to probe in a more intelligent manner," said TSRI Professor Raymond Stevens, who was a senior investigator for the new research.

The studies were published in two papers on March 21, 2013 in Science Express, the advance online version of the journal Science.

Pioneering Important Molecular Structures
Stevens's laboratory at TSRI has pioneered the development of techniques for determining the 3D atomic structures of cellular receptors -- particularly the large receptor class known as G protein-coupled receptors (GPCRs).

GPCRs sit in the cell membrane and sense various molecules outside cells. When certain molecules bind to them, the receptor's respond in a way to transmit a signal inside the cell.

"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," said Jean Chin of the NIH's National Institute of General Medical Sciences, which partly funded the 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 affected by these drugs and will offer a valuable framework for designing safer and more effective medicines."

Serotonin receptors are no less important. "Nearly all psychiatric drugs affect serotonin receptors to some extent, and these receptors also mediate a host of effects outside the brain, for example on blood coagulation, smooth muscle contraction and heart valve growth," said Bryan Roth, a collaborator on both studies who is professor of pharmacology at the University of North Carolina (UNC).

Untangling Two Serotonin Receptors
Roth's laboratory teamed up with Stevens's as part of the National Institute of General Medical Sciences (NIGMS) Protein Structure Initiative.

For this project the two labs also worked with the laboratories of Professors Eric Xu and Hualiang Jiang at the Shanghai Institute of Materia Medica, part of the Chinese Academy of Sciences.

"By collaborating with the Chinese teams we were able to complete a much more thorough study and get the most out of our fundamental structural results," said Stevens.

In the first of the new studies, co-lead author Chong Wang, a graduate student in the Stevens laboratory, and his colleagues determined the structure of the serotonin receptor subtype 5-HT1B, the principal target of several drug classes. (5-HT, or 5-hydroxytryptamine, is a technical term for serotonin.)

The team produced the 5-HT1B receptor while it was bound by either ergotamine or dihydroergotamine -- two old-line anti-migraine drugs that work in part by activating 5-HT1B receptors.

With the help of the special fusion protein, nicknamed BRIL (apocytochrome b562RIL), Wang and colleagues were able to stabilize these structures and coax them to line up in a regular ordering known as a crystal.

X-ray crystallography revealed, at high resolution, an atomic structure of 5-HT1B with a main binding pocket and a separate, extended binding pocket.

Read the full article here

Receptor may hold key to Multiple Sclerosis treatment

This image shows the A2A adenosine receptor (in red) abundantly expressed in the central nervous system (CNS). The blue colour identifies the nuclei of cells in the CNS.

A receptor recently discovered to control the movement of immune cells across central nervous system barriers (including the blood-brain barrier) may hold the key to treating multiple sclerosis (MS), a neuroinflammatory disease of the central nervous system.
 

In MS, immune cells enter the central nervous system and attack and destroy the myelin sheath surrounding the axons of nerve cells in the brain and spinal cord, resulting in blindness, paralysis, incontinence and many more symptoms.

The research, appearing last month online and in print June 1 in the Journal of Immunology, reveals how the A2A adenosine receptor expressed on blood-brain barrier cells acts as a gateway, allowing immune cells to enter the brain, where they can cause havoc in people with MS.

The blood-brain barrier is composed of specialized cells that selectively prevent substances from passing from the bloodstream into the brain.

"We found that expression of this A2A adenosine receptor is important for regulating the entry of cells into the brain; whereby its activation allows immune cell entry and its inhibition blocks entry," said Margaret Bynoe, associate professor of immunology at Cornell's College of Veterinary Medicine and senior author of the paper, which was also selected as a featured publication in the "In This Issue" section of the journal, where the top 10 percent of manuscripts are featured. Jeffrey Mills, a postdoctoral associate in Bynoe's lab, is the paper's lead author.

In this study, the researchers used mice where the A2A adenosine receptor was knocked out and then infused those mice with normal immune cells from wild-type mice expressing the A2A adenosine receptor.

This produced chimeric mice expressing the A2A receptor on immune cells, but not on blood-brain barrier cells.

Without A2A receptor on blood-brain barrier cells, the normal immune cells failed to effectively infiltrate the central nervous system, and thus, these mice were protected and developed less severe symptoms of MS-like disease.

"The absence of the A2A receptor on blood-brain barrier cells is similar to the effect of pharmacologically blocking the receptor with antagonists [drugs], which also protected mice from MS-like disease," Bynoe said.

"The implications of these findings are that, potentially, modulation of this receptor can be beneficial for future treatment of MS," she added.

Journal reference: Journal of Immunology  

Provided by Cornell University

Research Claims Ritalin Improves Ability to Learn

Research Claims Ritalin Improves Ability to Learn

Ritalin (methylphenidate), a drug prescribed for millions of children who have attention deficit hyperactivity disorder (ADHD), appears to improve the ability to learn by enhancing the speed of learning. Currently, Ritalin is prescribed to help inhibit impulsive behaviour, which in turn can improve a child’s ability to focus on tasks.

The new finding is the result of research by investigators at the University of California, San Francisco (UCSF). It is significant because it lets scientists know that Ritalin impacts and improves behaviour through two specific types of neurotransmitter receptors rather than just one. Neurotransmitters are chemicals that act as messengers to allow neurons to communicate with each other.

Previously experts knew that Ritalin enhanced the activity of the neurotransmitter dopamine receptor known as D2, which controls the ability to stay focused on a task. The new research shows that another dopamine receptor called D1, which is involved in the ability to learn and learning efficiency, is also affected by Ritalin. Apparently the drug produces these benefits by strengthening the ability of the neurons to communicate with each other at their meeting points, called synapses.

These new findings may allow researchers to develop more efficient drugs to treat ADHD and to improve the ability to focus and learn more efficiently, according to Antonello Bonci, MD, principal investigator at the Ernest Gallo Clinic and Research Center and professor of neurology at UCSF.