Science Signaling Podcast for 6 June 2017: Calcium signaling and dry mouth

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Sci. Signal.  06 Jun 2017:
Vol. 10, Issue 482, eaan8004
DOI: 10.1126/scisignal.aan8004


This Podcast features a conversation with Indu Ambudkar, senior author of a Research Resource that appears in the 6 June 2017 issue of Science Signaling, about how activation of the cation channel TRPM2 is involved in radiation-induced dry mouth. Patients who receive radiation therapy for head and neck cancers often develop dry mouth as a side effect, and this condition is frequently permanent. Radiation does not kill cells in the salivary gland, yet it causes the acinar cells of the gland to reduce the amount of saliva they secrete. Liu et al. found that radiation-induced activation of the cation channel TRPM2 triggered cleavage of the endoplasmic reticulum Ca2+ sensor STIM1, thus inhibiting store-operated Ca2+ entry and interfering with saliva production. These findings identify proteins that could potentially be targeted to prevent dry mouth in patients undergoing radiation therapy.

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Length: 12 min; file size: 8.3 MB; file format: mp3


Host – Annalisa VanHookWelcome to the Science Signaling Podcast for June 6th, 2017. I'm Annalisa VanHook, and today I’m talking with Indu Ambudkar about how activation of the cation channel TRPM2 is involved in radiation-induced dry mouth. (1).

When patients receive radiation treatments for head and neck cancers, they often develop dry mouth as a side effect. Unfortunately, this loss of salivary gland secretion can become permanent. These patients don’t initially show any gross morphological changes in the salivary gland, and the radiation doesn’t kill the secretory cells of the gland, so there’s no obvious anatomical explanation for the failure to secrete saliva. In a paper published in Science Signaling this week, Indu Ambudkar and her colleagues shed some light on how radiation inhibits saliva production. They show that radiation-induced activation of the cation channel TRPM2 interferes with a calcium signaling pathway that’s necessary for saliva production. Ambudkar spoke to me from the National Institutes of Health in Bethesda.

Interviewer – Annalisa VanHookDr. Ambudkar, welcome to the Science Signaling Podcast.

Interviewee – Indu AmbudkarThank you very much, Annalisa.

Interviewer – Annalisa VanHookHow common is it for patients who are receiving radiation therapy for head and neck cancers to develop dry mouth?

Interviewee – Indu AmbudkarSo, I would say it is pretty common. In the US, typically 40,000 to 50,000 people receive head and neck radiation for treatment of cancers. And typically about 80% of these patients will develop some sort of a dry mouth condition. And at least 40% of these patients go on to have an irreversible loss of their function, so they'll have persistent dry-mouth condition.

Interviewer – Annalisa VanHookAnd I'd just like to clarify here that the salivary glands that we're talking about here aren't being specifically targeted by the radiation. What's being targeted is the head and neck cancer, and the salivary glands are affected just because they happen to be near the target.

Interviewee – Indu AmbudkarYes, most often that's the case, because most of these patients have oral cancers or they may have cancers in their esophagus or head and neck region. There are, of course, some patients who have tumors within their salivary glands, and then that would be a different case altogether. But yes, in these other cases, the salivary glands just happen to be in the field of the radiation, and so they suffer sort of bystander effects of the radiation treatment.

Interviewer – Annalisa VanHookThey're just a casualty of treating a nearby tumor.

Interviewee – Indu AmbudkarExactly, yeah.

Interviewer – Annalisa VanHookDry mouth is more than just an annoyance. It can also cause medical issues, correct?

Interviewee – Indu AmbudkarYes. We don't think about how important saliva is because it's just something there in our mouth and, you know, we don't really consider all its properties. It's only people who don't have saliva [who] really understand how useful it is. Saliva, which is made up of water and the protein, and it's got a certain viscosity, and this then helps to coat all our oral surfaces, including the teeth and the mucosal surface. And that protects it, of course, from drying up, and it also has a lot of antibacterial/antiviral agents in the saliva; there are a number of enzymes and proteins, and in the absence of such proteins, you can develop infections within the oral cavity, canker sores, the cavities in the teeth, and there will be inflammation of the mucosal tissue in the mouth. But, apart from that, your quality of life goes down because the whole process of eating, which involves, you know, tasting—so, saliva actually helps you to taste the food. It also helps you to chew the food and swallow. So, all these processes are going to be affected. And so you have patients who have, you know, who are undergoing radiation and chemotherapy, and they won't be able to eat properly. And it is just not a good quality of life for the patients.

Interviewer – Annalisa VanHookIt had previously been shown that radiation can activate the anion channel TRPM2, which allows calcium to flow through this channel into the cell. And you've shown that radiation-induced activation of TRPM2 is involved in dry mouth. Do you know exactly how radiation activates that cation channel?

Interviewee – Indu AmbudkarYes, actually we do know that. Basically, radiation causes the generation of reactive oxygen species, which we also call ROS, you know, and increases in ROS inside cells can lead to the generation of a metabolite inside a cell, which is called ADP-ribose or ADPR for short. And this ADP-ribose can be generated at two places inside a cell—one is in the nucleus. So, if the nucleus undergoes DNA damage, then there is an enzyme called PARP—poly ADP-ribose polymerase—which gets activated, and this then leads to the generation of ADP-ribose. And the other place that ADP-ribose can be generated is in mitochondria—again, in response to increased ROS. So the ultimate requirement for the activation of TRPM2 is the increase in intracellular levels of ADP-ribose. And ADP-ribose binds to TRPM2 and directly gates the channel.

So the TRPM2 channel is not modified by the reactive oxygen species or other products of oxidation, but it actually senses the cellular levels of ROS through this metabolite, which is the ADP-ribose. And so, how do we know that? Well, we can block PARP activation—the enzyme PARP, there are inhibitors to block it. And if you block PARP activation in cells, typically you also block TRPM2 activation. And this has been shown in neuronal cells in a number of neuronal diseases. It was also shown in certain types of lymphocytes where also you have ROS generated through inflammatory processes, and we showed it in the context of radiation.

Interviewer – Annalisa VanHookSaliva is secreted by the acinar cells of the salivary gland. And the ability of these cells to secrete saliva is dependent on a process called store-operated calcium entry, which is a phenomenon in which the endoplasmic reticulum is stimulated to release calcium, and then that causes plasma membrane calcium channels to open, which allows calcium to flow into the cytosol. How does activation of TRPM2 by radiation interfere with that calcium signaling system, with store-operated calcium entry?

Interviewee – Indu AmbudkarYeah. So actually, that is the mechanism that we finally kind of revealed in this new study. So, store-operated calcium entry requires plasma membrane channels, which are activated by a protein called STIM1, which is in the endoplasmic reticulum membrane. And it is STIM1 that senses the concentration of the calcium within the ER lumen. So, if STIM1 decreases or the STIM1 gets modified in any way, that is going to directly affect the store-operated calcium entry. And what we have shown in this new study is that downstream from activation of TRPM2, there is a protease that gets activated. This protease is caspase-3. And caspase-3, in this case, is targeting STIM1 and cleaving STIM1. So, the active form of this protein is much decreased in the cell, and therefore store-operated calcium entry is impacted. And what we showed is that the way TRPM2 activation leads to activation of this enzyme, caspase-3, is through a mitochondrial pathway. So, the mitochondria gets compromised, and that then leads to the activation of caspase-3, and then decrease in STIM1 due to STIM1 cleavage, which then causes a decrease in store-operated calcium entry.

Interviewer – Annalisa VanHookAnd then the acinar cells fail to secrete saliva.

Interviewee – Indu AmbudkarYeah, or at least they have much decreased levels of secretion, because the calcium that comes in through store-operated calcium entry is very important and the cell uses that calcium to regulate a number of critical ion transport processes. So, finally, the acinar cell establishes an osmotic gradient across its apical membrane, and this osmotic gradient drives water out of the apical membrane. So, without this osmotic gradient, the water cannot move out of the cell.

Interviewer – Annalisa VanHookIs there any way to use this information that you've learned to help cancer patients who suffer from dry mouth as a side effect of their radiation therapy?

Interviewee – Indu AmbudkarYeah, I think it's going to be a little bit difficult to help them recover the saliva secretion, and currently that's a huge focus of our field because, you know, there are already lots of patients who currently have dry mouth—they are suffering from dry mouth. And, of course, one of the ways we can help these patients is if we can do something to trigger the function back in the gland. And currently, there are gene therapy trials where a water channel, aquaporin-1, is being delivered into the gland, and that causes an increase—slight increase—in saliva secretion. And what we showed in this paper is we can actually deliver STIM1 back into the gland, and at least in the mouse model, that helped a little bit in the recovery of the function.

But our study actually reveals a lot more targets that might be useful to prevent such decrease in salivary gland function or loss of salivary gland function if the patients get treated before radiation. And PARP1, for example—the enzyme that I was talking about earlier, which is involved in generating ADP-ribose—that actually is a very useful target for therapy. So, if we might be able to block the activation of that enzyme in the gland, that might actually prevent the subsequent loss of STIM1 and also the loss of fluid secretion. And additionally, mitochondria could also be a target.

Interviewer – Annalisa VanHookWell, thank you, Indu, for speaking with me.

Interviewee – Indu AmbudkarWell, thank you very much. I enjoyed having this conversation and discussion about our work.

Host – Annalisa VanHookThat was Indu Ambudkar talking about a paper by Liu and colleagues from the June 6th issue of Science Signaling. You can read that paper online at stke.sciencemag.org .


The Science Signaling Podcast is a production of Science Signaling and the American Association for the Advancement of Science—Advancing Science, Serving Society. If you have any comments or questions, you can write to us at sciencesignalingeditors{at}aaas.org. I'm Annalisa VanHook. On behalf of Science Signaling and AAAS, thanks for listening.

Educational Details

Learning Resource Type: Audio

Context: High school upper division 11-12, undergraduate lower division 13-14, undergraduate upper division 15-16, graduate, professional, general public and informal education

Intended Users: Teacher, learner

Intended Educational Use: Learn, teach

Discipline: Cell biology, human biology, physiology,

Keywords: Science Signaling, caspase-3, dry mouth, endoplasmic reticulum, head and neck cancer, radiation therapy, salivary gland, SOCE, store-operated calcium entry, STIM1, TRPM2, xerostomia


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