THOMAS LIANG & ARJUN MEHTA

(Both authors contributed equally and share first authorship of this work)

he/him | age 18 | London, ON

INTRODUCTION

Epinephrine, also known as adrenaline, is a hormone and neurotransmitter that is responsible for the “fight or flight” response to stressful situations (Harvard Health, 2020). Some symptoms of an adrenaline rush include increased heart rate, heightened senses, rapid breathing, and the release of stored sugars and fats (Harvard Health, 2020). You may recall some of these symptoms the last time you were giving a public speech or being chased by a grizzly bear. To learn more about how this chemical messenger works inside your body, we will explore how epinephrine communicates with target cells, maintains homeostasis after systemic disturbances to the system, and its impact on cellular respiration.

Epinephrine and the Nervous System

Your nervous system is split into two main sections, each with their own subdivisions: the Central Nervous System (CNS) and the Peripheral Nervous System (PNS). The CNS consists of your brain and spinal cord and is primarily responsible for processing information (Khan, 2004). On the other hand, the PNS includes neurons throughout the rest of your body, including sensory and motor neurons (Khan, 2004). Broadly, the nerves from PNS send signals to the CNS or to the rest of the body based on output from the CNS (Alshak & Das, 2023). When you experience a large amount of stress (like facing a grizzly bear), your sensory neurons send a signal to the CNS, more specifically a portion of your brain called the amygdala, which subsequently sends a distress signal to your hypothalamus (Jansen et al., 1995; Understanding the Stress Response, 2020). In response, the hypothalamus then activates the Sympathetic Autonomic Nervous System (SANS), a division of the PNS solely responsible for stress-related functions (S.P. Jansen et al., 1995). The SANS utilizes norepinephrine (or noradrenaline), a neurotransmitter that allows for the transmission of signals throughout the nervous system (Simons & Simons, 2010). Here, neurotransmitters are a key part of the nervous system, acting as signal mediators. In addition to being a critical tool within the nervous system, norepinephrine triggers epinephrine synthesis in the adrenal medulla, located in the adrenal glands on top of the kidneys (Cleveland Clinic, n.d.).

Adrenal glands, as the name suggests, are responsible for the production of the epinephrine hormone, among other hormones. For context, hormones are the mediators of the endocrine system, your body’s chemical messaging system. The endocrine system communicates by directing glands to produce certain hormones, which in turn elicit chemical responses from specific cells (e.g., contracting of the muscle cells when in danger). Together, neurotransmitters from the nervous system, along with hormones from the endocrine system, help your body maintain homeostasis and activate the fight-or-flight response when necessary.

Secretion and Binding Mechanism of Epinephrine

Located above your kidneys, the adrenal glands are responsible for the production and release of some key hormones, namely epinephrine, norepinephrine, and cortisol. Epinephrine travels through the bloodstream and binds to its target cells, affecting the respective organs. To identify which cells to impact, the hormone binds to specific receptors on the cell, which are often transmembrane proteins (Cell Signaling, n.d.). The receptors of epinephrine and norepinephrine are known as adrenergic receptors, or adrenoreceptors. These adrenoceptors are a class of G protein-coupled receptors, which transmit signals through a G protein. G proteins are composed of three subunits (alpha, beta, and gamma) and are responsible for the binding of guanosine triphosphate (GTP) and guanosine diphosphate (GDP). They also serve as a “signalling port” by passing along chemical messages in a process known as signal transduction. In terms of organization, adrenoreceptors are categorized into alpha (α) or beta (β) receptors based on their downstream physiological response. These categories contain multiple subgroups of these receptors, such as α1, α2, β1, β2, β3 (14.4B: Adrenergic Neurons and Receptors, 2018). Generally, β receptors respond to lower concentrations of epinephrine/norepinephrine than α receptors (Feher, 2012). The level of complexity here is astonishing: while each signal transduction pathway could be discussed to greater lengths, this article simply hopes to provide a broad understanding of how they function collectively.

Epinephrine binds to both the alpha and beta receptors. Interestingly, smaller levels of epinephrine have a higher affinity for the β-receptors, whereas larger amounts tend to favor α-receptors (Dalal & Grujic, 2023). The binding of different alpha or beta receptors elicits various responses at the organ level: for example, binding to the α2-receptor leads to the inhibition of insulin release in the pancreas, while the β1-receptor causes an increase in cardiac output (14.4B: Adrenergic Neurons and Receptors, 2018). Overall, stimulation of all the adrenergic receptors will result in the sympathetic “fight or flight” response (Feher, 2012).

How does the fight or flight response affect your physiology? Let’s explore the processes in detail below:

The inhibition of insulin increases the rate at which glucose is metabolized for energy but decreases how quickly glycogen synthesis occurs (the process in which the liver stores excess glucose for future use).
a) This allows the body to keep glucose in the bloodstream for immediate needs rather than long-term storage.
Similarly, when the SANS is activated, an increased cardiac output is helpful in supplying adequate amounts of blood that is rich with oxygen and other essential molecules.
Another observation here is how you may breathe faster in stressful situations. This is because sympathetic stimulation results in an increase in respiration, which explains why you may take shorter, quicker breaths.
a) The increased amount of oxygen allows for more efficient cellular respiration, which maximizes your body’s chances of survival from an evolutionary standpoint.

Like all cell communication processes (Figure 1), the epinephrine ligand (the signaling molecule that initiates the intracellular change) starts by binding with the intended adrenoreceptor. As soon as G-protein molecules are activated, a cascade of signal transduction reactions is set off inside the cell, resulting in the activation of protein kinases (PKA). PKA then impacts transcription through phosphorylation and is responsible for some of the subsequent intracellular changes (14.4B: Adrenergic Neurons and Receptors, 2018, Cell Signaling, n.d.). Each pathway is mediated by various enzymes, such as phospholipase C, and the reaction coupling of adenosine triphosphate (ATP) drives the entire process forward. For further context, some of the individual effects of α1, α2, and β-adrenoreceptors are shown as well (Figure 2).

**Figure 1:** Simplified diagram of the signal transduction process after epinephrine binds to the adrenergic receptor in a target cell, involving activation of the PKA enzyme, to influence the transcription of DNA. Borrowed from (*Cell Signaling*, n.d.).

**Figure 2:** Simplified diagram depicting the numerous ways in which target cells are influenced by epinephrine and norepinephrine, depending on the signal pathways and phosphorylation cascade patterns that occur in the cell after ligand binding happens. Borrowed from (*14.4B: Adrenergic Neurons and Receptors*, 2018).

Applying Cell Signaling to Fight of Flight Responses

Now that we know how epinephrine binds to cells, what exactly does it do in our body? The binding of epinephrine and norepinephrine elicits multiple responses in cells, tissues, and organs throughout the body. These range from dilating our pupils, so that we can take in more light to better view our surroundings, to turning our skin pale, as blood vessels direct blood to more important parts of the body, to heighten our body’s senses (Cleveland Clinic, n.d). One of the critical responses that our body has during stressful situations is changing our cardiac performance (i.e., heart rate). This response is one of the major impacts of the hormone-cell binding processes previously discussed.

The cardiac system is intertwined with the SANS, as indicated by the broad distribution of sympathetic nerve endings in the heart (S.P. Jansen et al., 1995). As discussed, cardiac performance is controlled by the activation of β-adrenergic receptors in the heart and PKA (Bers & Despa, 2009). This leads to the phosphorylation of several Ca²⁺ cycling proteins, resulting in stronger and faster contractions and relaxations of the cardiac muscle (Bers & Despa, 2009). Furthermore, β-adrenergic receptor stimulation increases depolarization potentials, which essentially allows for signals to be sent faster throughout neurons, and thus through the body. It also influences conductivity of potassium ions in the neuron, in addition to the activation of calcium uptake. Subsequently, it increases the spontaneous calcium release in pacemaker cells – specific cardiac muscle cells that control the rhythm pulses of the heart via depolarization (Wei et al., 2023). This rapid depolarization “instructs” the sinus and atrioventricular cardiac nodes to cause the heart to contract and release blood at a varied pace. This ultimately contributes to arrhythmia, or irregular heartbeat, during the fight or flight response (Bers & Despa, 2009).

In summary, the epinephrine and norepinephrine bind to the cardiac tissue. The activity induced by norepinephrine is a bit faster due the direct connection between the SANS and cardiac tissue. This results in several shifts in your heart rate to increase the speed at which it contracts and relaxes, potentially contributing to an arrhythmia. But why do our bodies need to increase their heart rate? Our muscles need more oxygen in stressful times, as we’re preparing to engage in some form of physical activity, whether it be running away or fighting back against something. As such, our body increases the oxygen that we intake by increasing airway sizes, constricting blood vessels, and increasing our heart rate. Ultimately, these processes increase the amount of oxygen that our muscles can receive (Harvard Health, 2020). Next, let’s examine the “energy currency” of our body that fuels all the necessary organs, tissues, and cells –adenosine triphosphate (ATP)!

Cellular respiration is essentially our body’s way of converting a glucose molecule into carbon dioxide and water, whilst also producing a molecule called ATP, utilized by many bodily processes. These processes include transport, mechanical, and chemical work. Thus, it’s incredibly important for us to obtain glucose from the food we eat. When glucose is not available to us, our body cannot undergo cellular respiration, depleting ATP, leading to the body’s required homeostatic processes performing at lower than ideal levels (Khan, 2004).

Epinephrine has another function that we have not touched upon yet, and that’s its ability to influence metabolic processes. Epinephrine and norepinephrine have been shown to have a profound impact on metabolic processes, by stimulating the mobilization of glucose and free fatty acids; which can be used to undergo cellular respiration, providing energy to the rest of the body (Verberne et al., 2016). Epinephrine attaches itself to α1- and β2-adrenoceptors in the liver and skeletal muscle tissues, stimulating glucose production in the liver and depressing endogenous insulin secretion (Verberne et al., 2016). In addition, epinephrine stimulates liver (hepatic) glucose production and lipolysis (glycerol and free fatty acids are produced from triglycerols), while decreasing glucose usage in the rest of the body, ensuring that only the areas critical to your survival can obtain it, such as your circulatory, respiratory, and muscular systems (Verberne et al., 2016). Your urinary system, for example, will have to wait until after the aggressive bear issue is resolved. During a stressful and potentially life-threatening situation, it is advantageous to have a surplus of glucose molecules readily available in the bloodstream. This allows for higher rates of ATP synthesis, so that processes that are critical for survival can be sustained.

CONCLUSION

The fight or flight response is our body’s natural reaction to danger. Epinephrine, as a hormone and neurotransmitter, plays a significant role in alerting the sympathetic nervous system in preparation for potential threats. Upon release from the adrenal glands, epinephrine rushes through your bloodstream to bind to α-androgenic and β-adrenergic receptors. This ultimately triggers the production of protein kinases, which in turn impact transcription and other processes at the cellular level. On a larger scale, this influences a multitude of processes throughout the body, including heart rate. Furthermore, epinephrine releases glucose and fatty acids, which stimulates increased rates cellular respiration, to satisfy greater energy requirements. Ultimately, the fight or flight response is a complex yet carefully crafted system, which is the result of thousands of years of evolution. We hope that you will be able to recall this article in the future and the intricate processes occurring within you - especially the next time that you must decide between fighting or running away from a hungry animal.

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The Effects of Epinephrine and Norepinephrine in the Fight or Flight Response