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If you zoomed in on the Big Potassium, or BK, ion channel inside a neuron, you might see it become activated through phosphorylation by protein kinase A. However, if you looked at that same ion channel in endocrine cells, you could see its activity, the voltage-gated ferrying of potassium, being inhibited by the same act of phosphorylation.

The conundrum of how the same mechanism acting on a protein can produce two completely different outcomes is at the heart of Mike Shipston’s research at the University of Edinburgh.

Mike Shipston pictured here at the University of Edinburgh’s Anatomical Museum.Nick Callaghan

After earning an undergraduate degree in physiology from the University of St. Andrews in 1989, began examining mechanisms of signaling pathways and regulation as a Ph.D. candidate at the University of Edinburgh, where he subsequently did his postdoctoral work as a Wellcome Trust advanced training fellow.

Now a dean of biomedical sciences and professor of physiology at the University of Edinburgh, Shipston combines mathematical modeling and wet lab techniques in an approach he calls integrative physiology to explore ion channels at the single-cell and cellular-systems levels.

A member of the editorial board of the Journal of Biological Chemistry since 2012, Shipston became an associate editor for the journal in March 2018 and chairs the JBC Reviews Committee. He spoke with John Arnst, an ASBMB Today science writer, about his work. The interview has been edited for clarity and length.

Your lab focuses on post-transcriptional and post-translational mechanisms. Tell me about that.

I’ve always been interested in the broad question of how we generate physiological diversity from a limited genome. And the variety of both post-transcriptional and post-translational mechanisms that are out there that allow you to generate proteomic diversity has always been a keen interest of mine and where I’ve focused efforts. This really took off for me in my own research when, several years ago, I was trying to understand how one of my favorite ion channels, the BK channel, is regulated by protein phosphorylation, particularly in endocrine pituitary cells that we were looking at.

At that time, we knew that the BK channel, or at least the pore-forming subunit, was encoded by a single gene. And in some systems — for example, in a lot of neurons — protein kinase A phosphorylation activated the channel, but in these endocrine systems I was looking at, protein kinase A inhibited the channel. So it’s actually a very simple question of how the same channel can be regulated differently by the same signaling pathway.

It turned out to be quite a simple mechanism — that the BK channel is alternatively spliced and there’s a single splice variant that acts as a molecular switch that determines whether the channel could be activated or inhibited by protein kinase A-dependent phosphorylation. We were then trying to work out how the splice variant might allow this regulation at the molecular level. And this led me into one of the focuses of the lab at the moment, the mysteries of this reversible lipid post-translational modification, with palmitoylation, also known as S-acylation (author’s note: the process of linking two molecules through a thioester bond), which controls this channel.

It’s always great when your research takes off with such a simple question — it’s so interesting that the BK channel action is completely location-dependent.

What I’ve always been interested in is that we have huge complexity. But very often, this huge complexity is driven by very simple rules that are put together in different combinatorial ways. And that’s a lot of what we’ve done in the past — trying to identify these simple rules that apparently give you this complexity.

A lot of stuff that we’ve been doing with S-acylation — we knew about that from the 1970s. But it’s been in the last decade that the tools for that have really exploded, so we can start to interrogate biochemical and physiological questions around that.

In our endocrine systems, there’s incredible heterogeneity from cell to cell in terms of how they respond, but that heterogeneity probably isn’t just noise; it probably is relevant to how the system works. So trying to probe those differences is important.

How did your earlier research lead you to interrogating post-translational mechanisms in endocrine systems?

When I was doing my Ph.D., I wasn’t an ion channel electrophysiologist or anything like that. I was doing biochemistry, cell biology and endocrinology. While doing that work, I realized that ion channels were fundamental targets for what I was looking at, and that actually led me to the Wellcome Trust. That was an advanced training fellowship that allowed me to develop skills in electrophysiology, which combined well with the molecular and biochemical tools that I had.

That’s where this interest in the ion channel biology really stemmed from. We’ve followed that by using the ion channels both as a model system to look at these mechanisms of post-transcriptional and post-translational modification and also as a way of understanding their physiological role in endocrine and other systems. So that’s really where it all stemmed from.

So that’s the integrative physiology approach?

My undergraduate training was as a physiologist; most of my postdoc training was using biochemical cell biological molecular tools. So for me, what I call the integrative physiology approach is really trying to understand a mechanism at multiple levels of scale. Ion channels are beautiful in that respect because they’re one of the few things where you can look at a single protein doing its job in real time.

That’s important, because we’re ultimately trying to understand what those mechanisms mean in health and disease: How is information encoded? How do you go from a defect in a channel or a signaling pathway that may regulate ion fluxes to control of diverse physiologies and then to disease states?

We’ve been increasingly trying to use predictive mathematical modeling approaches to help us understand both systems and mechanisms but also to allow us to get more quickly to wet lab experiments. Because ion channels don’t exist in isolation; they’re there with other signaling complexes.

How does that mathematical modeling inform what you’re next going to do in the lab?

A very specific example of that is the role we found for our BK channel in controlling excitability of a particular type of pituitary cell that’s involved in the stress response. One of the big challenges comes back to one of these splice variants I mentioned before; from a molecular perspective, it’s actually quite challenging to be able to quantitatively manipulate native systems and to really check out what each splice variant does.

We use a process called dynamic clamp, which allows us to mimic what we think the current would look like and then be able to automatically subtract or add that back to cells to see if our model of how we think the channel is working actually fits with the experiment. And that allows us to make predictions about what the properties of the ion channels that may regulate excitability need to be.

From that, without necessarily knowing the molecular nature of the channel, we can get an idea of what its properties are likely to be, which allows us to hone in to do either our genetic manipulations or our pharmacological manipulations.

That’s extremely helpful for ion channels that don’t exist in isolation — like if you’ve got a potassium channel that’s regulating something else, or like the interplay between calcium channels and other signaling pathways. So getting that more holistic sense of how ion channel flux is regulated is something you can only do by adding in that extra dimension of the modeling. Mike Shipston earned his Ph.D. and did postdoctoral work at the University of Edinburgh, pictured above, where he is now a dean of biomedical sciences and professor of physiology.

So using this technique and approach, what’s the frontier for your lab?

One of the key things for us is understanding different patterns of electrical excitability control, ultimately, and the secretory output of these pituitary cells — of the corticotrophs in particular, which are involved in a stress response, whose job is to integrate information from the brain and peripheral hormones like steroids and glucocorticoid hormones. It’s this interplay of different signaling pathways, how they ultimately end up controlling different ion channels, different signaling pathways within the cell, that allows the cell to make the decision about what its ultimate output is.

So you have this unique approach in the lab — how do you bring that to your role as a JBC associate editor, and how is the new role going?

As an AE, I must admit I’ve absolutely just loved it. I bring that approach by trying to identify those papers coming in that are applying different approaches to problems, and this also expands out into the wider role that I now have with JBC reviews. I try to highlight to the broader community how integrating, for example, modeling approaches alongside classical genetic and biochemical and pharmacological approaches can be a powerful way of interrogating fundamentals of biological chemistry and biological chemistry regulation. It’s been a very exciting role so far.

When did you first become involved with the journal?

I published my first paper in JBC when I was a relatively young postdoc in 1995. And I always remember, even at that point, being struck by how constructive the feedback was and realizing that the people who were doing the reviews were expert scientists working in the field. They weren’t trying to say, “Well, we don’t think this is a priority.” It was about, “Wow, this is a really cool idea, cool data that you’ve got; we’ve got some suggestions here about how it could be improved,” and you could have a rapport with them. And that’s what I’ve always loved about it.

Several years after that, I was asked to be an editorial board member, and I spent five years being an editorial board member, which I thoroughly enjoyed. It is a great way of exposing yourself to the wider research questions that you have, and you pick up more easily on cool techniques that people are publishing. Then a couple years ago, I was asked to do a second stint at as an EBM. And a year or so into that, (Editor-in-Chief) Lila Gierasch gave me a call out of the blue. I think there was this real connection with the vision she had, along with a team, about where JBC was going.

Over the last year or so, we’ve been helping drive a new initiative, JBC Reviews. They’re great both for the practicing researcher to keep updated and also to help educate the next generation. I use them in my undergraduate classes, and I use them in my postgraduate classes.

Speaking of education, do you have any words of wisdom for young scientists?

Always keep the big picture and longer-term in view, and make sure that you’re heading for that. You’ve got to be able to balance the real highs that you get when you get your next paper or your next grant out with the deep lows that you can sometimes go into, but if you if you keep your eye on the future of what you’re aiming for, that allows you to take risks and not to be too short-term, even though with a lot of funding issues you also have to be a bit short-termist.

One thing I think is very important, especially to junior folk, is about how you listen to advice. My recommendation is always listen to as wide a range of advice as you can but then make your own decision.

And I think something that’s also important for junior folks is taking time to mentor your staff and your trainees. Whether you’re a Ph.D. student and you might be mentoring an undergrad or you’re a junior faculty member who’s just starting in the lab with that first postdoc, the staff that you work with are your biggest assets, so what you need to do is invest quality time in them.

In the role I currently have, I get enjoyment and satisfaction out of seeing the development not only of my own students and my own staff in the lab but also of the faculty I work with. I get as much satisfaction out of that as my own research directions.

That’s heartening advice. What do you like to do outside of the lab?

I actually don’t get enough time physically in the lab, but my lab probably quite appreciates that, because I’m not disrupting them and annoying them too much, so they can get on with what they do. My day job as a professor of physiology and dean of biomedical sciences in Edinburgh keeps me pretty busy, and I also have a major interaction with our education and research institute in collaboration with in China that keeps me busy.

But what you’re probably asking for is what I do for relaxation. I love sports; these days, more watching than participating. I’m a big cricket fan, and my home team, England, just won the Cricket World Cup that was held in the U.K — the final was called the best game of cricket of all time. I know U.S. colleagues probably find cricket a bit of a mystery sport, but when I’m in the U.S. I love going to baseball games. Some other things I love are motor sports, playing golf and just relaxing, doing stuff with the family. And also reading good books — good biographies are a lot of fun.

To me, it’s very important to have activities that are not science-related. It keeps my mind fresh, I think.

I’ve always loved tinkering with stuff. I love doing practical things with my hands and keeping my DIY skills at home tip-top. A lot of it is just understanding how something works. I remember, as a kid, my dad was always into cars. He would take people’s cars and fix them. I love that sort of stuff, and part of it is just saying, look, here’s an engine, it’s incredibly complicated with all these thousands of pieces. But at a fundamental level, it’s pretty simple. You just want an explosion that moves a piece of metal, and that sends the wheels going. But there’s multiple components that need to work together. I think that interest in how systems operate from so many small pieces is built into my DNA.