Building bridges between people with Parkinson’s and basic research:
A mysterious story about how L-type calcium channels help dopamine be released…but only sometimes!
Hello! My name is Katherine and I am a neuroscientist at the University of Oxford funded by Parkinson’s UK. My work is focused on understanding the causes of Parkinson’s by researching the mechanisms that control dopamine release. A few years ago, I decided to write an accessible version of a scientific paper we had written, and found it such a rewarding experience I decided to do it again! You can read my previous post here.
The big picture:
We know that people with Parkinson’s don’t release enough of the chemical dopamine. Our speciality is measuring dopamine, and understanding the rules and machinery that controls how dopamine is normally released, with the aim of finding out what goes wrong in Parkinson’s.
My approach to investigating the causes of Parkinson’s is a game of “spot the difference”. I look for differences between groups of brain cells that die in Parkinson’s and those that don’t. Another approach we take is to look at differences between groups of people who have Parkinson’s and those who don’t e.g. genes or environmental factors, and see how these things change how dopamine-brain cells work.
A bit of background
For this study, we decided to focus on a part of the cell called the L-type calcium channel. The L-type calcium channel is a special gate that lets calcium into cells. When brain cells want to send messages to their neighbours, calcium comes in through these special gates, which is the trigger for brain cells to release their chemical messages. In order for dopamine-producing cells to send their messages, they need to let calcium come in, but if too much calcium comes in at the wrong place or time, it can kill the dopamine-cells. Some scientists think that when too much calcium comes in through the L-type calcium channel it damages dopamine-producing cells, which causes the symptoms of Parkinson’s.
Our results explained: Here they help, now they don’t!
To try and find the causes of Parkinson’s we study the dopamine-producing cells of mice. We look at parts of the brain that are similar to those we know are damaged in people with Parkinson’s. Using this approach we spotted that the L-type calcium channels only help dopamine be released in the area of the brain that’s sensitive to Parkinson’s. We know that both parts of the brain have the L-type channels, so why are they only working in the Parkinson’s-sensitive part?
To try to understand why the L-type calcium channels only sometimes help dopamine be released, we used a drug called isradipine. Isradipine stops L-type calcium channels from opening. We compared how much dopamine was released from mouse brains before and after adding isradipine. If isradipine decreased the amount of dopamine released, it shows that the L-type calcium channels were helping dopamine to be released.
Let’s use some diagrams to help visualise this…
A) In this picture when the dopamine-cell gets the signal to send a message (“knock knock”) the L-type calcium channel opens and lets calcium in, and then dopamine comes out. If we stop the L-type calcium channel from opening with isradipine (key), the calcium can’t come in through the L-type calcium channel and less dopamine comes out. Here the L-type calcium channel is helping dopamine to be released
B) In this picture, the L-type calcium channel doesn’t open when the dopamine-cell gets the signal, but dopamine still comes out. If we add isradipine(key) the same amount of dopamine comes out. Here the L-type calcium channel is not involved in dopamine release.
We did these experiments in lots of different conditions, to understand what decides when L-type calcium channels help dopamine to be released. We focused on genetic factors associated with getting Parkinson’s (e.g. alpha-synuclein and GBA) and parts of dopamine-cells that lots of scientists agree might make them vulnerable in Parkinson’s (e.g. dopamine transporter and less-calbindin [if you are interested in these terms there is more information about them in the accessible manuscript]).
Our results showed that when we measured dopamine from mice that we made more like people with Parkinson’s; L-type calcium channels were working to help dopamine be released (i.e. cartoon 2A), but when we measured dopamine from mice we made less like people with Parkinson’s L-type calcium channels stopped being involved in dopamine release (cartoon 2B).
One of the most interesting factors that affected if L-type calcium channels helped dopamine release, is sex: L-type calcium channels were more likely to be helping dopamine be released in male than female mice. Men are more at risk of getting Parkinson’s than women, but very little research compares male and female mice, and it’s only recently that researchers have used female mice at all. We think that this is a problem, firstly it is ignoring an important risk factor for Parkinson’s, but also it means that information about which treatments may or may not work in women with Parkinson’s will have been missed.
What does it all mean?
There are still lots of questions to be asked about how L-type calcium channels help dopamine to be released from these brain cells. Our next steps are to try and understand:
- Are L-type calcium channels damaging dopamine-producing cells?
- Or are L-type calcium channels signalling when cells are already damaged? (i.e. acting as the canary in the coalmine!)
We think this will help us to understand if we should be trying to stop L-type calcium channels from working to protect against Parkinson’s (if statement 1 is true), or if we should be using L-type calcium channels to find the cells and people at risk (if statement 2 is true). If statement 2 is true, we want to find ways to help the damaged cells so they can keep working and we can stop Parkinson’s in its tracks.
If you would like to know more about this research you can read the accessible version of the manuscript or the published scientific manuscript.
