In this video Dr. Goldstein introduces the learner to catecholamines including a memorable analogy that will help students recognize the chemical structure of a catechol.
Now I am going to get into my favorite topic which is, “what do catecholamines look like and how do they work?” Remember norepinephrine and adrenaline are two of the key chemical messengers of the sympathetic system. I think of catecholamines as catechols, they have a chemical structure and the chemical structure has two adjacent hydroxyl groups on a benzene ring and so the two hydroxyl groups kind of look like the pointy ears on the head of a cat. So catechols look like cats. Now catecholamine, like norepinephrine for instance or dopamine, is a catechol, but it’s got this hydrocarbon tail and it ends in this amine group or ammonia group which has kind of an ammonia smell. So, I think of a catecholamine as the entire cat from head to tail in its litter box – that is a catecholamine. And here is how a catecholamine synthesis happens. There are only three catecholamines in the body: dopamine, which is an important chemical messenger in the brain, norepinephrine, and adrenaline or epinephrine. You can see the only difference between dopamine and norepinephrine is this beta hydroxyl group. Remember you need DBH, dopamine beta hydroxylase, in order to make norepinephrine and this is where that hydroxyl group is. And then adrenaline just means that you add a methyl group to this “N” (the amine group), so the enzyme that would convert norepinephrine to epinephrine is Phenylethanolamine N-methyltransferase, right there, transferring a methyl group.
Here is how these three catecholamines work in the body, they work differently. In general, the brain has three ways to control what is going on inside. One, which you talked about a lot, is neurotransmitters. A neurotransmitter is released from a nerve terminal and it acts directly on a target cell in that organ. Adrenaline is a hormone, so adrenaline gets released into the bloodstream and then is swept to a whole variety of organs. Dopamine is a different type – it works outside the brain in a different way. It’s called an autocrine paracrine substance. It’s made in, released from, and acts locally on the same or nearby cells. It’s called autocrine paracrine substance. So, the three catecholamines, at least outside the brain, the three catecholamines have three different mechanisms of action: neurotransmitter, hormone, autocrine paracrine substance.
This is important because L-DOPS, which gets turned into norepinephrine in all organs that possess a particular enzyme – norepinephrine raises the blood pressure and it raises the plasma norepinephrine level, but norepinephrine is a terrible hormone. And so the mechanism of increase in blood pressure with droxidopa, it’s called NORTHERA, is not from the hormonal action of norepinephrine. Norepinephrine is a neurotransmitter and it’s actually a research topic: how does blood pressure increase with droxidopa? It’s not from the increase in norepinephrine levels in the plasma because it’s such a crappy hormone compared to adrenaline.
Remember the catecholamines work by way of receptors that are on the target cells. Beta adrenoceptors are especially important. Adrenaline stimulates an enzyme called adenylyl cyclase which results in activation of cells in the heart. The same hormone by way of beta receptors relaxes skeletal smooth muscle, and why that is frankly I’ve never really figured out. But classically adrenaline stimulates the heart, increases heart rate and so forth by way of occupation of beta receptors (there are three types). Alpha receptors are especially important in the blood vessel walls so adrenaline also tightens blood vessels and so does norepinephrine by way of alpha receptors. And there are two subtypes of alpha receptors and subtypes of each one. I can tell you that people have spent their entire careers working on this, these distinctions and identifying these receptors. In fact, Bob Lefkowitz, who discovered the down regulation of beta receptors by Isoproterenol or drugs that you use for asthma (you know if you overuse them, you get tolerant to them), for discovering the mechanism of that he shared a Nobel Prize in 2012.
Acetylcholine is very different chemical. Here is a quiz for you: is acetylcholine is a catechol? No, it’s not a catechol – where are the two pointy ears? Is it an amine? Well sort of – you’ve got this nitrogen there, but you notice that it has got four parts, it is attached four ways, that makes it something called quaternary amine. Not sure it works the same way as a catecholamine from that point of view, but it is correct that all of the messengers of the autonomic nervous system do involve a nitrogen compound. Acetylcholine is broken down by an enzyme called acetylcholinesterase, which doesn’t exist, I don’t think, inside the neurons but it exists in the extracellular fluid. So, the main way that acetylcholine is broken down is by an enzyme. As you’ll see, the main way that catecholamines are broken down is not necessarily by an enzyme.
This is the plant that is the source of atropine, a muscarinic cholinergic blocker. I think it’s called Atropa belladonna – I think. Belladonna from the Latin for good-looking woman. And I think what the tradition is, is that women who have dilated pupils are supposed to be more attractive, something like that. There is something about the dilation of the pupils that is associated with sort of a pleasant attractiveness, something like that. I think that’s why professional poker players wear sunglasses. They don’t want to show that their pupils are dilating when they look at their cards and they’re good cards. Okay, so that is atropine and it classically causes mydriasis that just means dilated pupils.
David S. Goldstein, M.D., Ph.D
Chief, Autonomic Medicine Section
NINDS, National Institutes of Health