New Methods For
Screening Drugs Could Help Chronic Pain Sufferers - New Understanding
How Menthol Affects Ion Channels in Transfer Pain Signals
New research has found a novel method that could lead to potential
advances in pain therapy. New methodologies could help scientists
understand how molecules, like menthol, affect the function of proteins
that form ion tunnels found in the cell membrane. These tunnels form a
channel that allows specific ions to pass or move across the membrane.
The Director of the Research, Ardem Patapoutian, said “"Because our
ability to sense temperature is closely linked to our ability to sense
pain, it is not surprising that the misregulation of
temperature-activated ion channels can result in chronic pain
syndromes." Patapoutian is an associate professor at Scripps Research
and member of GNF. He went on to say “In fact, some of these ion
channels are considered targets to treat chronic inflammatory and
neuropathic pain indications. Understanding how small molecules such as
menthol affect the function of these proteins could be crucial in
designing future drugs that can either activate or block them."
When the channels are activated, they open allowing an influx of calcium
ions into the axon. Then an electrical signal alerts the neuron, which
relays the message to the brain.
Lead author, Michael Bandell, said, "It's a well established method to
mutate individual amino acid residues in an ion channel protein and
examine the effect that these mutations have on the channel's function.
However, the laborious nature of these experiments limits the number of
mutant ion channels that can be made and analyzed. Our new
high-throughput screening methodology allowed us to analyze 14,000
mutants out of which we isolated five that specifically affected menthol
activity. Our experiments yielded significant insights into the
functional elements of TRPM8 ion channel protein that would have been
difficult to obtain using other mutagenesis methods."
The scientists utilized this novel mutagenesis and high-throughput
screening approach. The study assayed 14,000 TRPM8 mutants to find
mutants that were not enhanced by menthol but were otherwise functioning
normally. The scientists' analysis pinpointed a potential interaction
site for menthol, as well as a site that translates binding information
to ion channel activity.
Since the methodology can be used to screen for activation or
inhibition, it could prove to be useful as a general method to analyze
the mechanism by which drugs can activate or inhibit ion channels or
other receptors. According to the report appearing in the advanced
online version by the journal Nature Neuroscience, the new methodology
could be used to identify amino acid residues in certain ion channel
proteins and G-protein coupled receptors (proteins involved in
stimulus-response pathways) that are involved in the interaction with
small molecules that affect their function.
There are an estimated 86 million Americans that suffer from chronic
pain. Many sufferers may obtain either over-the-counter (OTC) remedies
or prescription remedies. Others may turn to alterative methods
including acupuncture or acupressure. Pain is the number one reason for
doctor’s visits according to authors of the book Where it Hurts and Why,
Angela Sehgal and Kim Ortloff.
By Dan Wilson
Best Syndication Staff Writer
Books about Pain
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