Channeling Out The Heat

By: Hanson Tam

Stand under the sun on a sweltering summer day, and your skin becomes sticky with sweat. We take perspiration for granted, often dismissing it as an annoying bodily function. Yet it is profoundly important for mammalian thermoregulation. Sweating allows you to evaporate off excess heat and maintain a steady temperature in the narrow range required for survival. If a person gets too hot, he or she suffers from hyperthermia, which manifests as muscle cramps, nausea, and delirium. On the other hand, if a person’s core temperature falls too low, hypothermia sets in, leading to heart and lung abnormalities (1).

Although scientists have long understood the macro-level phenomena of thermoregulation, the molecular basis for how we sense and respond to temperature is still being discovered. Broadly speaking, heat and cold sensors send signals to the brain, which then instructs parts of the body to respond appropriately (2) These sensor proteins constitute an exciting area of current research. A group of scientists in Germany recently demonstrated that they could significantly lower a mouse’s body temperature by manipulating neurons that have the protein TRPM2 (3). Published in the journal Science, this groundbreaking discovery not only advances our understanding of thermoregulation but also suggests possible treatments for a variety of diseases.

THE BIG PICTURE

Before we dive into the fascinating but microscopic world of molecular biology, let’s take a moment to explore some of the human body’s large-scale responses to hot and cold. After all, there is no point in sensing temperature if we cannot do anything to change it!

When overheated, humans not only sweat but also effect changes in the circulatory system. The cutaneous blood vessels in our skin expand. Meanwhile, vessels associated with our inner organs contract. These two responses position more warm blood near the skin’s surface, allowing heat to easily radiate out into the environment. Complementing these phenomena is an increase in cardiac output—the volume of blood pumped per minute—in order to maintain proper blood pressure after vessel dilation (2).

As expected, our response to cold is the exact opposite. Cutaneous blood vessels constrict to minimize the amount of heat lost to radiation. But conservation is often not enough, leading us to generate heat through metabolism. One mechanism is brown adipose tissue (BAT), a type of fat whose primary purpose is thermoregulation. When BAT receives nerve signals, its mitochondria digress from their usual task of generating energy and instead allow energy leaks to warm up the body. A second mechanism is shivering, which uses the contraction of muscles to burn chemical energy and release heat (2).

The current model for thermoregulation involves sensors in the skin and internal organs. When stimulated by heat or cold, they signal through neurons to the central nervous system (CNS), specifically the preoptic area (POA) of the hypothalamus in the brain. The hypothalamus combines signals from the body with signals from its own temperature sensors. Upon processing all these electrochemical stimuli, the brain decides whether the body needs to generate or lose heat (2,3). But what are the magical sensors that allow us to measure temperature in the first place?

GATEKEEPERS OF SENSATION

The surprising answer is transient receptor potential (TRP) channels. The TRP channel family consists of ion channels involved in many sensations, including sight, smell, taste, hearing, and touch. They are embedded in cell membranes and when open, allow positively charged calcium ions to flow through. In humans, there are 27 such proteins, divided into seven families based on structure. One of their most interesting properties is that a single channel can be activated by many different stimuli. For example, TRPV1 responds to heat, chemicals, and immune signaling molecules known as cytokines (4).

Although the exact mechanisms of TRP channel activation are mostly unknown, recent studies have provided clues. The basic idea behind chemical activation is that a molecule, called a ligand, binds to a crevice on the complicated structure of the closed channel. The electrostatic attractions between the ligand and its binding site cause a shape change that propagates through the entire protein, resulting in an open conformation. A similar paradigm governs TRP channels responsive to voltage and temperature. At some threshold, electrical potential or thermal energy triggers select protein domains to modify their structure. These changes combine to open the channel (5).

Another way of thinking about temperature sensitive TRP channels is in terms of the energies of the closed and open conformations. It is a fundamental tenet of thermodynamics that a system prefers its lowest possible energy state. Let’s consider the case of TRPV1, which is activated by heat. At room temperature, the closed conformation has much lower energy than the open, so the channel stays shut. But at 50 ºC, the energies are reversed, and open is more favorable. Ions are now allowed to flow through the channel (5).

How does the opening and closing of TRP channels lead to neural signaling to the brain? It turns out that TRP channels mainly allow Ca2+ ions through and that calcium signaling plays a role in many cellular functions (4). A large sudden change in the balance of positively and negatively charged ions across a cell membrane creates an electrochemical current that propagates through a cell (6). For channels situated on neurons, this pulse would start a chain of signal relays that would eventually reach the brain.

THE MURINE CHILL FACTOR

Research in this area has long been focused on TRP channels expressed in the periphery, or anatomical locations away from the brain. But intuitively, a temperature measurement from the skin should be less important than a temperature measurement in the brain itself (3). Such was the motivation for the Science paper Song and colleagues published on TRPM2.

As its acronym implies, TRPM2 is a TRP channel. The structures of TRPM2 and TRPM8 are very closely related, and since the latter is known to be activated by cold, scientists were interested in the possibility that the former is also a temperature sensor protein. In 2006, Togashi et al. showed that TRPM2 can be activated by warmth, in addition to previously reported stimuli such as metabolic molecules and chemicals indicative of cell stress (6). And in 2009, Csanday and Torocsik performed a detailed analysis of TRPM2’s mechanism of action (7).

Previous research has shown that there are warm-sensitive neurons (WSNs) in the POA of the hypothalamus, the thermostat of the human body. When the POA is heated, WSNs fire electrical pulses more rapidly. When the POA is cooled, WSNs slow down and stop (3) The new research done by Song et al. elucidates the cause of this phenomenon. Through a process of elimination, the authors homed in on TRPM2, which is highly expressed on certain WSNs. They found that only neurons that had normal TRPM2 experienced calcium influxes when shocked with heat. When the protein was knocked out, or rendered nonfunctional, calcium signaling did not happen (3).

After establishing the threshold of TRPM2 activation at 38 ºC, which is slightly above normal body temperature, the German research group wanted to test the channel’s functionality in living mice. Since TRPM2 is a heat sensor, the scientists expected it to carry out cooling functions. They genetically engineered mice with an on/off switch for specifically the neurons expressing TRPM2. When the switch was turned on by administration of a drug, the TRPM2+ neurons fired, and body temperature dropped to a stunning 27 ºC (3). Using infrared imaging, Song and colleagues took an amazing video that shows heat dissipating from the mouse and warming up the environment (8). Conversely, when the switch was turned off, the TRPM2+ neurons were inhibited, and body temperature actually rose to 39 ºC, suggesting that TRPM2 normally cools our bodies continuously (3).

FIGHTING DISEASE WITH A THERMOMETER

Understanding the function of TRPM2 has opened up new possibilities for treating disease. In the Science paper, the authors directly tested the role of the channel in fever response. They injected PGE2, a fever-inducing mediator, into normal mice and knockout mice that lacked TRPM2. Those without the heat sensitive protein had fevers there were on average almost one full degree higher.3 While there are significant differences between mice and humans, these data suggest that manipulating TRPM2 activity could be a way to treat temperature-related conditions. In addition, artificial activation of the ion channel could be beneficial to recovery from trauma. Lowering body temperature reduces tissue damage from heart attacks and stroke.2 If doctors were able to directly stimulate TRPM2 channels in the hypothalamus with a new drug, they would no longer need to use ice baths to fight the body’s generation of harmful heat (9). Meanwhile, controlled inhibition of the channel might increase metabolism and counter obesity. With the brain less sensitive to high temperatures, it is plausible that the body could burn off more fat and not mind generating heat (2).

TRPM2 is also implicated in the immune system. When Song et al. injected inflammatory cytokines into mice, those without the channel had higher fevers (3). TRPM2’s expression in the bone marrow, where many immune cells develop, lends further credence to the idea that the heat sensitive protein modulates our response to infection (4). A study from 2013 found that macrophages—cells that consume pathogens in the blood and tissue—lacking TRPM2 produced a weakened inflammatory response. Thus, a drug that blocks TRPM2 might help treat certain autoinflammatory conditions such as gout, atherosclerosis, and Alzheimer’s disease (10).

Diabetes is yet another area where thermoregulation, disease, and TRPM2 cross paths. Scientists have shown that the channel is expressed in rat pancreatic β-cells, from which insulin is secreted. β-cells that were exposed to heat released extra insulin and underwent Ca2+ signaling. And when TRPM2 was blocked, the heat responses faded away (6). While the exact implications are unclear, these data suggest that a TRPM2-targeted treatment might be useful in diabetes.

THE BIOLOGICAL THERMOSTAT

Thermoregulation is remarkably logical. It is basically an input-output system. The thermostat in the hypothalamus integrates temperature measurements from throughout the body. Through complex electrical circuits, the computer that is our brain directs our sweat glands, blood vessels, and skeletal muscles to perform the necessary work. The most fascinating part of it all may be the input mechanism. Translating temperature into biological activity seems like a daunting task. But nature created TRP channels—switches that open and close at predefined thresholds of activation. As these molecular gates direct ion traffic in and out of our cells, temperature becomes encoded in the electrical firing of neurons.

Thanks to recent discoveries, we are beginning to grasp the secrets of how we constantly adapt to changing temperatures. It may not be long until we gain the ability to set our own thermostats to treat diseases and save lives.

Hanson Tam ’19 is a sophomore in Lowell House, concentrating in Molecular and Cellular Biology.

WORKS CITED

[1] Cheshire, W., Jr. Auton. Neurosci. 2016, 196, 91-104.

[2] Morrison, S. F1000Research 2016, 5, 880.

[3] Song, K. et al. Science 2016, 353, 1393- 1398.

[4] Venkatachalam, K.; Montell, C. Annu. Rev. Biochem. 2007, 76, 387-417.

[5] Baez, D. et al. Curr. Top. Membr. 2014, 74, 51-87.

[6] Togashi, K. et al. EMBO J. 2006, 25, 1804-1815.

[7] Csanady, L.; Torocsik, B. J. Gen. Physiol. 2009, 133, 189-203.

[8] Science News. Thermostat Neurons Cool Off a Mouse. YouTube [Online], Aug. 25, 2016. https://www.youtube. com/watch?v=ixD-Ej95fFU (accessed Sep. 9, 2016).

[9] Chodosh, S. Resetting the Body’s Thermostat with a Molecular On/Off Switch. Scientific American [Online], Aug. 26, 2016. http://www.scientificamerican.com/article/resetting-thebody-s-thermostat-with-a-molecularon-off-switch/ (accessed Sep. 9, 2016).

[10] Zhong, Z. et al. Nat. Commun. 2013, 4, 1611.