Our sensation of taste involves a whole cascade of reactions before it finally results in a nerve signal reaching the brain. The process is triggered when a tastant molecule, such as sugar or caffeine, binds to a g-protein coupled receptor on the cells of the taste bud. This causes the protein receptor to deform slightly, which results in the activation of an enzyme, phospholipase. This in turn releases calcium ions, which bind to the TRPM5 ion channel, opening the channel to allow sodium ions into the interior of the cell. This flow of ions into the cell causes the cell to depolarise, which introduces another chain of reactions that ultimately leads to the nerve signal being produced.
The TRPM5 ion channel is important, because it acts as an amplification of the signal to produce the signals noticed by the brain. "This channel is like a volume control for the taste cell," says Dr Raymond Salemme, CEO of Redpoint Bio. "There's a completely proportional response to the activity of this channel."
The more sodium ions that can flow into the interior of the cell, the greater the taste sensation produced from any single tastant molecule. Certain chemicals, called modulators, can either open or block this passage, controlling the degree of this amplification and determining how strongly we sense the tastant molecule.
Redpoint Bio is now trying to discover new modulators which could hide the taste of bitter drugs, or enhance a sweet taste without having to add greater volumes of sugar. However, to do this the company needed a systematic way to single out compounds that would have an effect on this channel, from chemicals which have no impact.
The solution, originally investigated by Robert Margolskee and exclusively licensed from the Mount Sinai School of Medicine, came in the form of an assay, made from genetically modified cells, altered to express the TRPM5 channel. When a dye is introduced into these cells, they fluoresce green light depending on the electrical activity of the cell, with a cell containing a high potential providing a stronger output than a cell that is electrically neutral.
If a compound successfully alters the activity of the ion channel, it will either increase or decrease this electrical activity, and the change can be observed by measuring the light output of the cell's fluorescence using a camera. "The whole point is that you can analyse 384 samples at once," says Salemme, providing a fast and effective way of screening many chemicals. "The new patent will allow us to continue to work [in this area] in the event that others obtain related patents around technology in the area."