Boo! AHHHHHHHdrenaline! Instead of trick or treat, let’s talk fight or flight and the chemistry behind the spook of a fright! When it comes to foods, most of the focus at Halloween time is on sugar. But, when it comes to adrenaline, you have a protein letter to thank – yep, thank tyrosine for Halloween! Without this amino acid you couldn’t make L-DOPA, and without L-DOPA there’d be no dopamine, and without dopamine you could have neither noradrenaline nor adrenaline!

video added 10/31/21

Before we dive into our tale of hormones (chemical messengers released from glands) and neurotransmitters (chemical messengers released from the nervous system), let’s clear up this whole name pain. Adrenaline is the same as epinephrin and noradrenaline = norepinephrine, BUT adrenaline is different from noradrenaline (it has an extra methyl (-CH₃) group). Adrenaline and epinephrine mean the same thing even etymologically – the words just come from different languages and were named by different scientists. There are different accounts of early discoverers – William Bates in 1886 found something produced by the adrenal gland and then in 1895, Polish physiologist Napoleon Cybulski found it. In 1901, Japanese chemist Jōkichi Takamine purified it from adrenal glands, named it adrenaline (Latin “ad” (near) + “renal” (kidneys)) & patented it – and then Europe went with it. But another scientist, John Abel, had already prepared an adrenal extract and called it epinephrine (Greek “epi” (on top of) + “nephros” (kidneys)). It turns out that this didn’t even contain active adrenaline, but the US went with it. So now it’s a big confusing mess of names! But just remember that while adrenaline and epinephrin are the same adrenaline and noradrenaline are different! They also can play different roles, but both serve as critical chemical messengers called catecholamines. And hopefully by the end of this post you’ll get what I means! 

Let’s start by talking about how cells in your body communicate through chemistry. Your body has billions of cells and they need ways to talk to one another. Nerves are great if you want to send a signal to one specific place – like to tell the end of a single one of Stephen Colbert’s eyebrows to move up. 🤨 You don’t want to send that “move” message to the whole eyebrow, or the other eyebrow, or definitely not the entire body. To get this level of specificity you have to have a direct connection.

Nerve cells called neurons communicate with other neurons and/or muscle, gland, etc. cells by passing messages really short distances. One neuron releases a chemical called a neurotransmitter (there are lots of different ones, including noradrenaline) into the gap between the 2 of them (synapse) and then receptors on the second one bind that neurotransmitter and relay a message into the cell.

But what if you want to send a message to your entire body? If you see a bear – or a beautiful peak on your chromatograph indicating you’ve gotten a yowza yield from your protein purification prep – you don’t just want to raise an eyebrow. You want your body to stop doing “housekeeping” work like digesting and keeping your fingertips warm and instead focus on doing what you need to do to run away – or run off to fill your friends in on your exciting news! 

Unlike the nervous system, which requires all the “wiring” to be laid out, like having one of those “direct” phone lines, which are great if you only want one person to get your message (and no wiretaps allowed!), the ENDOCRINE SYSTEM is more like radio. It sends a message out to everyone, but you can only get it if you have your radio tuned in to the right wavelength. Instead of sending out waves, the endocrine system sends out chemical messenger molecules called hormones from “broadcast stations” called glands and only cells expressing the matching receptors can hear the message and respond (with various responses depending on the type of cell getting the broadcast).

Hormones get secreted into the bloodstream so they pass by all your cells, but only cells with the right receptors can respond (like having your radio tuned to the right wavelength). These receptors are proteins that are embedded in your cells’ membrane. Like all proteins, the instructions for making them are written in your DNA “blueprint” – so each cell has the instructions and thus could make it if they wanted to, but, thanks to lots of regulation, only certain cells do. And they can make more or less at different times to “ramp up” or “calm down” sensitivity & responses to signals. 

Problem is, the signal still has to get to them, and signals that can easily go through the blood have a hard time getting into the cells that need them (even if they have the right receptor) and signals that can slip right into their target cells have a hard time getting there. Why? SOLUBILITY!

It’s important that these molecules are able to travel through the blood, so they need to be soluble. In order for something to be soluble, the solvent molecules (dissolver like water) have to want to bind to the solute (the molecule you want dissolved) more than they want to bind to other solute molecules. And the solute molecules have to want to bind those solvent molecules more than they want to bind each other and whatever else is floating around in there.

The reason people are always looking for evidence of water on other planets is that all life we know of is water-based because water’s an awesome solvent – for a lot of things – but not all things.

Many hormones *are* water-soluble because they’re HYDROPHILIC (water-loving/water-loved) – hydrophilic hormones include peptide, protein, glycoprotein, & catecholamine hormones (this is the class adrenaline & noradrenaline are in). So they travel fine through your bloodstream, to the cells they want to target. But in order to get from the blood into your cells, they have to get through your cells’ lipid membrane.

Oil and water don’t mix so the lipid (basically oil coat) your water-y cells are surrounded in keeps the inside of the cells (cytoplasm) separate from the outside of your cells. To get things through, your membrane has things like pores which provide channels and pumps which use energy to actively transport them (sometimes in exchange for pumping something out (we call these co-transporters) that let through specific things.

But hormones usually take another option -> don’t let the molecule into the cell but make sure the message gets passed along – some molecules bind surface receptors -> these receptors are embedded in the membrane so a change to the outside part (like a hormone binding) can cause the receptor to shape-shift, causing something to happen on the inside side.

This can set off a signaling cascade that amplifies the signal & gets it where it needs to go. Often these cascades involve kinases which relay the message through phosphate-adding (a phosphate group is a phosphorus surrounded by oxygen and it’s negatively-charged so it can cause proteins to act differently). The receptors themselves can be kinases (as is the case for insulin) or they can signal intracellular kinases (as is the case for growth hormones). Messages can also be passed into the cell by “2nd-messenger” systems like cyclic adenosine monophosphate (cAMP) or lipid messengers -> inositol triphosphate (IP3) and DiAcyl Glycerol (DAG). You just need something where hormone binding on the outside can be relayed to the inside of the cell.

Other type of hormones, steroid hormones (like cortisol, testosterone, estrogen) and thyroid hormones like thyroxine *can* get through the membrane because they’re hydrophobic/lipophilic (water-excluded/lipid-loved). Once inside, they can also get through the membrane surrounding the nucleus where the DNA is kept. Here they bind to an intracellular receptor -> hormone-receptor complex binds hormone response elements in DNA -> can directly affect the expression of genes (e.g. make more of this, less of that). But steroid hormones have a hard time traveling around in the blood, because water hates them – so they travel through the blood by piggybacking on on transport proteins that shield them from their nemesis.

If a cell has the receptors and gets the signal, the actual response you get will depend on the type of cell getting the signal – cells specialize in different things and get different input combos (there are lots of other hormones and stuff whose messages also have to get taken into consideration) so your skin cells will respond differently than your muscle cells, and the muscle cells in your blood vessel walls will respond differently from those in your calves. Plus, as is the case with catecholamines, you can have multiple types of receptors that can bind the same molecule but elicit different responses. So there’s a lot of possibilities coming from these little molecules!

Here’s a little bit about what adrenaline & noradrenaline do, and then I’ll tell you more about how they’re made. 

Adrenaline & noradrenaline can act both as “neurotransmitters” AND “hormones” – the “job title” just refers to whether a chemical messenger is released from a nerve cell or from a gland – it has nothing to do with the actual messenger molecule that’s released. So when noradrenaline is released from nerves in your sympathetic nervous system we call it a neurotransmitter. But when it’s released from your adrenal gland we call it a hormone. 

Adrenaline is primarily “only” a hormone because it’s almost all released from your adrenal gland, with just a little bit being made & used by a group of neurons in your brainstem; but noradrenaline is the main neurotransmitter used by the sympathetic nerves in your cardiovascular system. Even under un-stressful conditions, it plays an important role in making sure your heart and blood vessels don’t relax too much (which they would without noradrenaline because the counterbalancing parasympathetic nervous system tells them to relax)

There are different types of adrenergic receptors (aka adrenoreceptors), different cells express different combos, and they can elicit slightly different responses…. oi vey! But they do have something in common – they’re all “G-protein coupled receptors” (GPCRs) which means that when the catecholamine binds, a little “G protein” attached to the receptor on the inside-the-cell part swaps a GTP (like ATP but a different RNA letter) for the GDP it did have and then interacts with other things to relay the message. 

Different receptors, even if they all bind the same things, can thus set off different signaling pathways. End result? Get your heart to beat faster, your liver to stop storing glucose as the storage molecule glycogen, and instead break down glycogen (glycogenolysis) and release the resulting glucose into the bloodstream. Speaking of bloodstream, different receptors can lead to blood vessels constricting or widening. You want some of your blood vessels to constrict (vasoconstriction), which, like pinching a hose, raises blood pressure and restricts blood flow to less important regions like your fingertips. And then, to help you shunt the blood to where you want it, like your calve muscles which need blood to run, you want those places to widen instead of tighten their blood vessels. So cells in those places express receptors that get them to “loosen up” (vasodilate) when they get the catecholamine call. 

So there’s a lot of concerted action that’s coming from that one molecule and leading to the “fight or flight” response and there’s no simple answer for what they do. And so I’ll leave that level of complexity for hormone & neuro people…. And get back into my comfort zone a bit & talk about the biochemical make-up (and making) of these messengers! 

As I teaser-ed you with above, catecholamines come from the amino acid tyrosine (abbreviated Tyr or Y). more on it here: http://bit.ly/tyrosinehormones  

We normally think about amino acids as protein letters. There are 20 (common) ones and they have a generic backbone part they can use to link together into long polypeptide chains (which can fold up into proteins) as well as unique “side chains” or “R groups” that stick out kinda like charms on a charm bracelet. These unique side chains (some big, some small, some charged, some neutral, etc.) are great for giving different proteins different properties. And they’re also good for other things. So amino acids aren’t “just” protein letters. And perhaps no amino acid shows this better than tyrosine which, in addition to serving as a precursor to those catecholamines, also serves as the basis for making thyroid hormones and the skin pigment melanin. 

Tyrosine’s side chain is the same ring-y thing as that of another amino acid, phenylalanine (Phe, F), with a crucial difference: Tyr has a hydroxyl (-OH) group plopped on (straight across from where the ring attaches to the methylene linker attaching it to the generic backbone). This helps make Tyr & Tyr-based produces soluble so they can travel between neurons & throughout our blood in their chemical messenger duties! Tyrosine can come from your food or from making it from phenylalanine (in fact, about half of the Phe you eat is actually used to make Tyr). (but you can’t make phenylalanine so Phe is “essential” while Tyr is “nonessential” in the dietary sense). 

The first step on the path from Tyrosine to adrenaline is adding ANOTHER -OH to the ring to give you L-DOPA. (The L refers to the stereochemistry (which way the atoms stick off from each other – L-DOPA comes from L-tyrosine, which is the “normal” version of tyrosine). This second OH make it even more soluble, and it gives it a dope name – we call benzene-based (6-sided aromatic ring) molecules with 2 -OH groups “catechols” and since it also has an amine (NH₂/NH₃) group, we call L-DOPA and its derivatives CATECHOLAMINES. (so that’s where that name comes from!)

Since (-OH) is called a hydroxyl group, we call this “gifting of a hydroxyl group” hydroxylation. Although is it really proper gifting if you steal from molecular oxygen (O₂) to give to the tyr-ed? I’ll let you grapple with that moral quandary and instead get back to the mechanism at hand…

This specific hydroxylation is helped out by an enzyme called Tyrosine Hydroxylase (TH), which is a homotetramer (4 copies of the same protein chain working as a team), which is itself helped out by a cofactor (non-protein helper molecule that the protein enzyme binding to to give it “superpowers”) called TetraHydroBiopterin (THB)

L-DOPA is turned into dopamine by removing the carboxyl group – the thing that made an amino acid an acid. But you still have the amino part, and you have the catechol part. So dopamine is still characterized as a catecholamine. This decarboxylation is catalyzed by an enzyme called DOPA DeCarboxylase (DDC). It also decarboxylates other aromatic amino acids, so another name for it is Aromatic Amino acid DeCarboxylase (AADC). This uses a vitamin B6-derived cofactor called PyridoxaL Phosphate (PLP)

Now that you have dopamine, what to do? Some cells in the substantial nigra (part of the basal ganglia in your midbrain) stop here and use dopamine as a neurotransmitter as is, where it plays important roles in reward responses. But, otherwise, the next step is turning it into noradrenaline (aka norepinephrine). This is accomplished by adding another OH,  but this time to one of the non-ring carbons. And this is catalyzed by Dopamine β-Hydroxylase (DBH). DBH is another tetramer, but a heteromeric one (not all its subunits are the same). And It, too, uses a cofactor, but it uses ascorbate so it’s vitamin-C dependent.  

Noradrenaline can be used as-is. Or it can be further processed to form adrenaline by adding a methyl (-CH₃) group onto the end of of it. That’s done by Phenylethanolamine N-MethylTransferase (PNMT), with the extra methyl coming from the cofactor S-AdenosylMethionine (SAM). Only cells with PNMT can do this conversion, and PNMT is not found in most neurons (though it is made from a small group of neurons in the brainstem). Instead, most of it is in the adrenal gland (specifically in the inner part called the medulla) & its activity is regulated by corticosteroids – hormones like cortisol made in the outer part of the adrenal gland (the adrenal cortex)

Breaking down catecholamines requires catecholamine-O-methyltranserase (COMT) & monoamine oxidase (MAO). If MAO sounds familiar it’s likely because MAO inhibitors can be used as antidepressants.

I hope you’ve found today’s post to be a “treat” – Happy Halloween!

article for that PLP mechanism figure: https://www.frontiersin.org/articles/10.3389/fmolb.2019.00004/full 

more on topics mentioned (& others) #365DaysOfScience All (with topics listed) 👉 http://bit.ly/2OllAB0⠀

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