Pain sensations and other information are mainly conducted through our nervous system as electrical signals. Yet at decisive moments, this information is converted to biochemical signals, in the form of specific molecules. To develop future drugs against pain, researchers must understand the details of what happens at the molecular level when pain signals are converted from one form to another.
When the electrical signal reaches the end of one nerve cell it is converted into a biochemical signal, in the form of calcium. In turn, an increase in calcium triggers the release of signalling molecules called neurotransmitters. This biochemical signal is received by the next nerve cell, that converts the signal back into electricity. Along this chain of information transfer in the nervous system, one class of proteins is of particular interest: the voltage-sensitive calcium channels. These channels are like molecular machines that sense electrical signals and then open to allow calcium to flow into the nerve cell.
Pain treatments could be improved
In the current study, researchers at Linköping University have focused on a specific type of calcium channel called CaV2.2, that is involved in the transmission of pain signals. In fact, these channels are more active during chronic pain. They are specifically located in the ends of sensory nerve cells.
Drugs that dampen their activity reduce the communication of pain signals from the sensory nerve cells to the brain. Such drugs exist, but there is a catch: a drug that blocks CaV2.2 completely has such severe side-effects that it needs to be given directly into the spinal fluid. Drugs that decrease the number of CaV2.2, like gabapentin, do not reduce chronic pain very efficiently. Another class of drugs that exploit a natural mechanism to decrease the ability of CaV2.2 to respond to pain signalling are the opioid drugs, like morphine and heroin. While very effective at blocking pain, they are also addictive and can cause devastating dependency.
“Calcium channels are very attractive drugs targets for pain treatment, but today’s solutions are inadequate,” says Antonios Pantazis, associate professor at the Department of Biomedical and Clinical Sciences at Linköping University, who has led the study published in the journal Science Advances.
Reluctant proteins
The researchers studied the mechanism by which opioids decrease CaV2.2 activity. It has been known for a long time that opioids release molecules called G proteins, which directly bind to calcium channels and make them “reluctant” to open. But how does this happen?
“It is as if G-protein signalling causes the channel to need more ‘persuasion’ – in terms of stronger electrical signals – to open. In our study, we describe at the molecular level how this is done,” says Antonios Pantazis.
In the calcium channel there are four so-called voltage sensors that detect electrical nerve impulses. When the voltage is high enough, the voltage sensors move and make the channel open, so that calcium can flow through. The researchers used tiny light-emitting molecules to detect how these voltage sensors move in response to electrical signals. They discovered that G-proteins impact the function of specific voltage sensors, but not others, making them more “reluctant” to sense electrical signals.
“Our finding points to a very specific part of the large calcium channel that next-generation drugs can target to provide pain relief in a similar way to opioids. Instead of blocking the calcium channel completely, which is a less refined method, future drugs can be designed to fine-tune calcium channel activity in pain signalling,” says Antonios Pantazis.
It is hoped that future drugs designed to impact the CaV2.2 calcium channel can have a better pain-relieving effect and less side effects.
The research was funded with support from the Knut and Alice Wallenberg Foundation through the Wallenberg Centre for Molecular Medicine at Linköping University, the Swedish Brain Foundation, the Swedish Research Council, the National Institute of General Medical Sciences and Lions Forskningsfond.
Article: Voltage-dependent G-protein regulation of CaV2.2 (N-type) channels, Michelle Nilsson, Kaiqian Wang, Teresa Mínguez-Viñas, Marina Angelini, Stina Berglund, Riccardo Olcese and Antonios Pantazis, (2024), Science Advances, published 11 September 2024, Vol 10 (37), doi: https://doi.org/10.1126/sciadv.adp6665
