Pain signals travel through the nervous system with the help of proteins known as calcium channels, which play a crucial role in the process. Researchers at Linköping University in Sweden have identified the precise location of a specific calcium channel that modulates the intensity of these signals. This discovery could pave the way for the development of more effective drugs with fewer side effects to treat chronic pain.
Pain sensations and related information are primarily transmitted through the nervous system as electrical signals. However, at critical moments, these signals are transformed into biochemical signals, carried by specific molecules. To develop future pain-relief drugs, researchers need a detailed understanding of the molecular processes involved in this conversion.
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 signaling 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.
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 signaling are the opioid drugs, like morphine and heroin. While very effective at blocking pain, they are also addictive and can cause devastating dependency.
Investigating G Proteins and Calcium Channel Modulation
“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.
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 signaling 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 signaling,” 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 fewer side effects.
Reference: “Voltage-dependent G-protein regulation of CaV2.2 (N-type) channels” by Michelle Nilsson, Kaiqian Wang, Teresa Mínguez-Viñas, Marina Angelini, Stina Berglund, Riccardo Olcese and Antonios Pantazis, 11 September 2024, Science Advances.
DOI: 10.1126/sciadv.adp6665
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.
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