Researchers Develop Assay to Help Identify New Pain Medication Candidates

Scientists at the Scripps Research Institute (TSRI) in Jupiter, Florida, have developed a test that will help scientists identify new drug candidates for treating pain that have fewer side effects, like addiction. The study conducted by scientists in Scott Hansen’s lab at TSRI was recently published in Cell Reports.

Neurological drugs, like painkillers, are notoriously messy. They bind to targets throughout the brain and produce myriad undesirable side effects. One reason for this is that the tests, or assays, that researchers use to identify how molecules interact with certain receptors have been difficult to apply to ion channels, a type of structure that drives brain function. The Hansen Lab has overcome this limitation by developing an assay that will allow scientists to screen an ion channel, TREK-1, that is known to be involved in pain. 

Ion channels are proteins situated in the membrane of a cell. When they open, they allow ions to flow into or out of the cell, altering the cell’s electrical charge and, ultimately, its behavior. While most scientists agree that lipids inside the cell’s membrane have important roles in the cell’s function, the interactions between lipids and ion channels have been difficult to study due to a lack of applicable assays. 

“There’s this mystery about membranes and lipids,” said Scott Hansen, associate professor of molecular medicine at TSRI. “We’ve known that they are important regulators and potential targets [for drugs], and there just really wasn't an assay to screen them at the level needed.”

In order to conduct a high-throughput assay, scientists need to isolate the channels by solubilizing the environments surrounding them. Ion channels are found in the lipid membrane, which unfortunately is not soluble. Hansen explained that they’re like a clump of fat that won’t go down the sink when you’re trying to do your dishes.

Fortunately, Hansen and his team realized that like fat, once the lipid membrane could be broken up and solubilized with a little detergent, the channel could be used in a soluble assay. The team used the strategy in this study to show that a lipid called PIP2, which was thought to agonize the channel, is actually antagonizing—or blocking—it.

Next, the assay will be advanced to drug discovery and used to screen for possible drug candidates that will act on the receptor and may be useful in managing pain. TSRI is known for its pharmaceutical-grade drug-screening capabilities, and the technique is likely to be applicable for screening other ion channels.

In addition, the study provided evidence that these channels can be opened and closed by lipids, like PIP2. Scientists have long known that some ion channels are controlled by neurotransmitters binding to the membrane structure (ligand-gated ion channels). Hansen and his team have recently proposed one more way these channels are controlled. Lipids, which float throughout the lipid membrane itself, can bind to the receptors and cause them to open or close as well. Hansen calls these channels “lipid-gated ion channels.” This aspect of ion channel function opens a whole new set of questions about how our brains work.

In addition to Hansen, three other researchers worked on the study: Lead Researcher Cerrone Cabanos of TSRI, as well as Miao Wang and Xianlin Han of the Sanford Burnham Prebys Medical Discovery Institute in Orlando, Florida.

The work was supported by an NIH Director’s New Innovator Award (1DP2NS087943-01 to S.B.H.).

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