Researchers Develop Light-Controlled Molecules to Switch Cell Activity

Cells are always sending signals. They use tiny electrical and chemical changes to talk to each other, respond to their surroundings, and stay alive. These signals must be carefully controlled. Too much or too little activity can cause serious problems.

Scientists often use drugs to study how cells work. But drugs spread unevenly inside the body. One cell might receive a high dose, while another gets very little. This makes experiments harder to interpret, especially inside real tissues.

Because of this, researchers have been searching for better ways to control cell behavior, ways that are fast, precise, and reversible.

Light has clear advantages. It can be delivered exactly where it is needed. It can be turned on and off instantly. And it does not mix or spread like chemicals do.

This idea led to photopharmacology, a field where drugs are designed to change their shape when exposed to light. In theory, light can then control whether the drug is active or inactive.

In reality, the approach has struggled. Most light-controlled drugs still depend heavily on concentration. If too much drug is present, light can no longer fully switch its effect.

The new study, published in Nature Chemical Biology, describes a different strategy. Instead of trying to control how strongly a molecule binds to a protein, the researchers focused on what the molecule does after binding.

They designed molecules that always bind tightly to their target. The difference is that one light-controlled shape activates the target, while the other blocks it.

This means that once enough molecule is present, activity no longer depends on dose. It depends only on light color.

The research focused on TRPC4 and TRPC5, two ion channels found in many parts of the body. Ion channels are tiny pores in the cell membrane. They allow charged particles, like calcium, to enter the cell.

Calcium signals control many processes. They help neurons send messages, muscles contract, and hormones get released.

TRPC4 and TRPC5 have been linked to pain, anxiety, kidney function, digestion, and brain activity. Despite this, their exact roles are still not fully understood.

Better tools were needed to study them in living systems.

The researchers started with xanthines, a group of molecules already known to bind very strongly to TRPC channels. Small chemical changes can turn these compounds from blockers into activators.

This made them ideal candidates.

To make them light-sensitive, the team added an azobenzene group. Azobenzene changes shape when exposed to different wavelengths of light.

Under ultraviolet light, it bends into one shape. Under blue light, it straightens into another.

Two main compounds were developed, called AzPico and AzHC.

The first tests were done in human cells grown in the lab. These cells were modified to produce TRPC4 or TRPC5 channels.

When ultraviolet light was applied, calcium rushed into the cells. This showed that the channels were active.

When blue light was used, the calcium signal dropped back down.

This switching could be repeated again and again. Even more important, it worked across a wide range of concentrations. Whether the drug level was low or high, light still controlled the outcome.

To confirm these results, the team measured electrical currents passing through the channels.

Using a technique called patch clamp recording, they showed that currents turned on under activating light and switched off under deactivating light.

This happened reliably, even when the drug concentration was increased. Normally, higher doses overpower light control. Here, that did not happen.

This confirmed that the molecules acted as true light-controlled switches.

To understand how this worked at a molecular level, the researchers used cryo-electron microscopy. This method allows scientists to see proteins at very high resolution.

They captured images of TRPC channels bound to both light-controlled shapes of the molecules.

The molecules sat in the same binding pocket in both cases. However, small changes in orientation altered how the channel behaved.

These subtle differences were enough to push the channel toward either an active or inactive state.

The next question was whether this system would work in real cells, not just engineered ones.

The team tested neurons taken from the mouse brain. These neurons naturally produce TRPC channels.

Light pulses triggered electrical responses in the neurons. When the same experiment was done in mice lacking these channels, the response disappeared.

This showed that the effect was specific and worked on natural proteins.

Chromaffin cells, found in the adrenal gland, release stress hormones like adrenaline. This process depends on calcium entry.

When the researchers applied the light-controlled molecules, hormone release could be switched on and off using light alone.

Blue light stopped the release. Ultraviolet light restarted it.

Cells without TRPC channels did not respond, confirming the mechanism.

The team also studied dopamine-producing neurons in the hypothalamus, a deep brain region involved in motivation and movement.

Using fluorescent calcium sensors, they watched how neurons responded to light.

Some neurons responded strongly to one compound but not the other. This suggested that TRPC4 and TRPC5 play different roles in the same circuit.

Such differences are very hard to detect using traditional drugs.

One of the most striking experiments involved mouse intestine.

Normally, intestinal muscles contract rhythmically to move food along. TRPC4 plays a role in this movement.

After blocking normal signals, the researchers added the light-sensitive molecule.

Ultraviolet light caused strong contractions. Blue light stopped them almost immediately.

This optical control worked repeatedly and without harming the tissue.

In biology, control is everything. Researchers need tools that are precise, reversible, and reliable.

Because these molecules depend on light color rather than dose, they avoid many common problems. Uneven drug distribution is no longer a major issue.

Once enough compound is present, light alone determines what happens.

The system still has limits. Ultraviolet light does not travel deeply into tissue and can cause damage with long exposure.

Future versions may respond to longer wavelengths that are safer and penetrate further.

Not all proteins can be controlled this way. Still, many ion channels and receptors may be suitable.

This study shows that light can be used as a precise biological control signal, even in complex living systems.

From single cells to whole organs, the same molecules worked reliably.

That consistency is rare and valuable.

As scientists continue to explore how living systems function in real time, tools like this may help answer questions that were previously out of reach.

The research was published in Nature Chemical Biology on January 16, 2026.