Today we know whole lot about different receptors in our body. Often we know which one to target for particular disease and how the drug molecules operate on the molecular level. But it’s always interesting to learn something new about how do we sense the world around us. What molecules make us aware of sight, taste, smell, hearing and touch? The paper in the latest issue of PNAS gives some new insights in the perception of sour taste.
It’s been well-known that sour taste comes from acidic media. However, the correlation between pH and sourness is not straightforward. Many strong acids with lower pKa (and hence pH in water) do not taste as sour as weak organic acids like acetic or citric acid. This paper sheds some light on why is that.
First, authors demonstrated that sour taste depends on intracellular rather than extracellular pH. They measured action potentials of cells isolated from sour-sensitive taste buds and noticed that small organic acids (acetic and propionic) induced more prominent response than much stronger methanesulfonic acid. The difference is due to higher membrane permeability of the former.
Next, deep sequencing supported by pharmacological inhibitory analysis revealed that potassium ion channels, specifically inward-rectifying KIR2.1, are responsible for the formation of action potential. Intracellular acidification inhibited the ion conductance through these channels, as authors showed by patch-clamp experiments. The ultimate evidence for the mechanism authors collected from conditional knockout mice lacking KIR2.1 channels in their taste buds, developed via floxed allelle thechnology.
So it seemed like the core sour-sensing molecule was identified. But when the authors conducted a control experiment with sour-insensitive cells, the intracellular acidification also inhibited K+ flow through KIR2.1 in the resting state but did not trigger any action potential, unlike in sour-sensing cells. So there must be something else in addition to KIR2.1 that helps us feel tartness.
At this place the authors confessed that so far they hid an important detail from the reader. In all previous experiments they inhibited direct proton inflow by adding Zn2+ to the extracellular medium. So when they didn’t add Zn2+, the difference between sour-sensitive and insensitive cells became apparent. Also it became apparent that sour-sensitive cells actually do respond to extracellular acidic pH, while insensitive cells don’t. And it appears that KIR2.1 inhbition due to the drop of cytoplasmic pH is acting synergistically and downstream of direct proton influx.
So in the end I was left with mixed feelings about the paper. On the one hand, it describes a really interesting discovery with a strong experimental evidence. On the other hand, the structure of the manuscript is kind of weird. I don’t understand what authors were aiming for by not revealing the important experimental detail until the description of the last experiment. It certainly wouldn’t help to the understanding of the results by a lay reader like me.