Category Archives: Common Receptors and Targets

Dopamine: Helps you Pick Up Chicks

Disclaimer:  There’s a  bit of brain lingo here.  If you and the ‘matter are cool, by all means, keep on keepin’ on.  If words like pontomesencephalotegmental complex freak you out, however, might I suggest this fun neuroanatomy review?


Oh, don’t sigh.  You know you like it.

Dopamine is a neurotransmitter synthesized in your brain from an essential amino acid called tyrosine.  You get much of your body’s tyrosine from your diet, notably from high-protein foods like cheeses, turkey, and pumpkin seeds.

But…why are we talking about dopamine?  Since it is one of our more prominent CNS neurotransmitters, dopamine is implicated in tons of neurological and psychiatric disorders.  Researchers toil every day to put their paws on what exactly dopamine is doing in the brain and spinal cord.  So I am sure all of them will appreciate me narrowing down thirty years of hard work into a very brief introduction to this complex and fabulous neurotransmitter, and the receptors it affects.

There are actually quite a few ways that dopamine helps you pick up baby chickens.

1) It helps you concentrate on something you want to do, like scooping up a yellow fluffball of joy.

2) It helps you recognize that picking up something fluffy is going to make you feel good.

3) It helps you control your movements so you gently pick up the baby fluffball instead of crushing it between your ruthless human paws.

4) It helps bring joy into your heart when you pick up that little baby chicken and it peeps at you.

5) It helps you remember that you might get some chick pee (bahaha!) on your hands, so you bring some hand sanitizer.

Anyway, as of NOW, we know dopamine follows a few different pathways in the brain. These tracts are lined with dopamine receptors D1 and D2 (and D3-5 but for now let me explain what I “know”, which does not include much about the other ones.  Enlighten me, I beg you.). The densities of these G-protein coupled receptors vary by location, which probably determines their varied actions.  Two very important receptor pathways are the mesolimbic/mesocortical tract and the nigrostriatal pathway.

Dopamine Pathways. In the brain, dopamine play...
(Photo credit: Wikipedia)

The mesolimbic/mesocortical tract originates in dopaminergic neuronal bodies in the ventral tegmental area of the brain.  As you may have observed from its name, it is actually two different tracts, but for now let’s just treat it as one.  It feeds dopamine to the limbic system and cerebral cortex and is often referred to as the “reward pathway”.  We use rewards (thank you Pavlov!) not only to learn how to get what we want, but to be able to recognize things that are harmful to us.  Much research has been devoted to the role of dopamine in addictive behaviors.  Additionally, an imbalance of dopamine in this pathway (especially in the prefrontal cortex) is one of the major prevailing theories of schizophrenia.

The nigrostriatal pathway originates in dopaminergic neurons in the substantia nigra. This pathway is important because it feeds dopamine to the striatum of the basal ganglia–a dense gathering of neurons that are responsible for learned automatic movements, like walking up stairs and feeding yourself.  Too little dopamine (or dopamine receptors) in this pathway can cause a disrupt in the extrapyramidal tract of motor neurons in your spinal cord.  The result is the rigidity and spasticity seen in Parkinson’s Disease.

*If you did not click on the links as you were reading, I urge you to do so for your own well-being.


Renin-Angiotensin System: Using “The Other Brain”

English: Overview of the renin-angiotensin sys...
(Photo credit: Wikipedia)

Not THAT “other brain”.

It is sometimes said that the kidneys are a human body’s “second brain”.  They do have an awful lot of work to do.  You probably already know that the adrenal glands on top of the kidneys are responsible for secreting a number of very important hormones.  You also know now that the nephron is the functional unit of a kidney, and that is where all the fun electrolyte action happens.

But did you know that the nephron itself excretes a hormone that culminates in vasoconstriction? This is one way that the kidneys compensate for low blood pressure or blood volume. The hormone is called renin, and it is awesome.

The Renin-Angiotensin-Aldosterone System (sometimes just called the Renin-Angiotensin system, or RAAS) is a chemical pathway.  Much like the metabolic pathways in your liver, RAAS consists of several substances converting into others through the action of enzymes.I love RAAS because it kind of thwarts the notion of separate organ systems, and just barges through four of them.  Stick it to the man, RAAS!  Here is how it works:

The glomerulus is the knot of capillaries that begin the process of filtration in the nephron.  Nearby, the juxtaglomerular cells carefully monitor the rate of blood flow into the tubule.  One of their main functions is to secrete renin in response to slowed blood flow.  This can be due to any number of things, but the kidneys “know” that they won’t be able to work properly without the right amount of filtration.

Once renin is released, it meets up with an inactive substance secreted by the liver, called angiotensinogen. (Just a quick aside, when you see that the name of a compounds ends in -inogen, it usually means it is an inactive precursor.  Something else has to cleave it or add to it to make it active!)  Renin cleaves (cuts off) a part of angiotensinogen, turning into the now active Angiotensin I.

Angiotensin I then meets up with an enzyme called, creatively, Angiotensin Converting Enzyme (ACE).  ACE turns Angiotensin I into Angiotensin II.  It is generally agreed that this process happens in the lungs, but that agreement will likely be turned on its head eventually, so let’s just assume for now. Although it is theorized that Angiotensin I has some effective properties of its own, our general concern here is with the effects of Angiotensin II, as they are quite varied.

Angiotensin II does a bunch of stuff.  I’ll just go ahead and list some of it:

1) Causes the blood vessels to constrict, especially those that lead to the nephron.  This allows the rate of filtration at the glomerulus (GFR) to remain constant even though there is less blood flow.

2) Signals the release of antidiuretic hormone (ADH aka vasopressin) from the posterior pituitary gland.

3) Signals the release of aldosterone from the adrenal gland.

The net effect of this system is a rise in blood pressure.  Antidiuretic hormone and aldosterone both hold on to water and electrolytes, keeping up the blood volume.  Vasoconstriction maintains the GFR.  The kidneys, once again, are happy.

But…what if the reason you have a reduced filtration rate is due to reduced cardiac output?  What if your heart is not getting enough oxygen and is not working its best as a pump? Do your kidneys, those little second brains, know this?


All they know is that not enough blood is getting to them.  So this compensation mechanism, as long as there is reduced cardiac output, will continue to vasoconstrict and hold water and salt.  This compensation mechanism will definitely reduce the amount of oxygen that is able to get to your heart when it needs it.  So you can see how this might be bad news for someone prone to a heart attack.

Lucky for us, pharmacology has a couple of tools to help us overcome this little snag.


Ball-and-stick model of the gamma-aminobutyric...
Ball-and-stick model of the gamma-aminobutyric acid (GABA) molecule. (Photo credit: Wikipedia)

Why say it three times?  Because if you really try, you can attribute almost ANYTHING your body does to GABA (it might take a little creativity, but work with me here).  It is a neurotransmitter with a receptor by the same name (If you are feeling cheated because no one was creative enough to make the name of the receptor more interesting, don’t fret. The people who name genes and chemical compounds have gone a little overboard).  GABA (gamma-aminobutyric acid) receptors are mostly in the CNS, and they are responsible for managing neuronal action potentials that control everything from the sleep-wake cycle to memory.

For now, we will focus on the GABA-A (I just call them GABAAAAAAAH, but I’m not positive that is a generally accepted pronunciation) receptors, the hypothesized focus of a group of drugs known as anxiolytics, amnesics, and sedative hypnotics.

GABA-A receptors are a special type of ligand-gated chloride channel, and one of their particularly special functions is that they are inhibitory to neurons.  That is, the influx of Cl- that they allow causes hyperpolarization, which reduces the possibility of an action potential.  So if, say, you are having some issues with overactive neurons (like epilepsy), GABA-A agonists might be prescribed to calm those suckers down.

The other cool thing about GABA receptors is that, although their main ligand is GABA (and a few other compounds), they have all of these little ports called allosteric sites.  Allosteric binding results in potentiation or inhibition of a receptor.  In the case of GABA-A, potentiating allosteric sites can be bound by many of the drugs in the sedative hypnotic and antiepileptic classes, including benzodiazepines, barbituates, and vodka (well, alcohol).

Potentiation (agonism) of the GABA-A receptor has lots of useful actions.  In anesthesia, it is used to make you sleepy and calm, to prevent nausea, and to help you forget much of what just happened to you (hallelujah!).  In psychiatry, GABA-A potentiation is useful for temporarily reducing severe anxiety.  In general medicine, GABA agonists are used to prevent seizures, stop status epilepticus (uncontrolled, continuous seizures), and as a sleep aid. As you can imagine, GABA antagonism results in quite the opposite reaction:  increased neuronal activity and wakefulness.

Nicotinic M Receptors: The Beach is That Way

So, as you may have guessed, Nicotinic M (Nm) Receptors are famous for their role in skeletal muscle movement!  They are all over the motor end plates at the neuromuscular junctions of our skeletal muscles.  So they are in charge of receiving the signals, via acetylcholine binding, to depolarize and contract! Nm Receptors have had a long history of being messed with in different ways, and it’s pretty awesome.  But I digress…

These receptors are Ligand Gated Ion Channels.  Remember those?  If not, check out “Our Friends the Receptors” in the Basic Pharmacology section.  The coolest thing about this type of receptor is that ligands (like Acetylcholine, or ACh) bind to them directly.  That means there is no chain reaction that must occur (like the “second messengers” in GPCRs, think of that game called “Telephone“).  The receptor simply changes its shape, and certain ions are allowed to flow in or out.  Genius! But why is it so important to have this kind of receptor at the Neuromuscular Junction?

Ligand Gated Ion Channels are FAST.  We need these because muscles need to quickly depolarize and repolarize to maintain a contraction or get ready for the next contraction.

Drugs that affect these receptors at the neuromuscular junctions either enhance the amount of ACh available (cholinesterase inhibitors), compete with ACh for binding (nondepolarizing neuromuscular blockers), or block ACh completely (depolarizing neuromuscular blockers).

Receptors never cease to amaze me.  Humor me for a moment and watch your fingers type something.  Then imagine how fast those ion channels are receiving signals and getting to work.  Incredible!  Now imagine what would happen if all of them were suddenly blocked.  Besides how awful that would be, can you think of a good use for that trick?

Detailed view of a neuromuscular junction: 1. ...
Detailed view of a neuromuscular junction: 1. Presynaptic terminal 2. Sarcolemma 3. Synaptic vesicle 4. Nicotinic acetylcholine receptor 5. Mitochondrion (Photo credit: Wikipedia)

The Renal Tubule: Target Practice!

Ah, the renal tubule: the convoluted master of filtration, reabsorption, and secretion.  Some parts of the renal tubule have so many receptors and ion channels that they start having really crazy names.  This is a great way to nerd out when you are otherwise procrastinating, but for the sake of time, there must be an easier way!  This is when we enter the realm of the target.

The renal tubule has four major drug targets:

1.  The proximal convoluted tubule

2.  The ascending Loop of Henle

3.  The distal convoluted tubule

4.  The collecting duct

The drugs that target the nephron are usually diuretics.  So, they target the tubules in such a way as to make more urine and release more fluid from your body.  Other drugs have the opposite effect to help you with, for example, an underactive antidiuretic hormone. Now would be a good time to review renal physiology if you are feeling a little rusty!

There is a great adage thrown around in physiology that really helps when you are looking at diuretics:  Where salt goes, water follows.  You see, it’s easy to get water out when you can just push out the salt.  But what if you need some of that salt (not to mention potassium and magnesium!)?  Ah, this is why we have different targets for diuretics!

To have a diuretic affect, drugs have to either promote or block receptors for a certain purpose.  Therefore, drugs that target the tubules for diuretic purposes…

1.  Block reabsorption, or…

2. Enhance secretion, or…

3. Block antidiuretic hormone (ADH)

So, if you are pushing out more fluid using these mechanisms, you will reduce blood volume, resulting in lowered blood pressure, lessened cardiac workload, and reduced edema!

Muscarinic Receptors: Blood Vessels, Sweat*, and Tears**

Sit back and relax after a meal, recline and let your heart slow down, feel the warmth of your extremities…and secrete those fluids!

Ewwwwww…secretions!!  Diaphoresis, urination, vasodilation, lactation, and all kinds sweaty gooey things coming out and doing their thing!  In a very crude and stunted way, this is a main function of the parasympathetic nervous system. 

Muscarinic receptors are usually what we are talking about when we refer to anything “cholinergic”.  This is because their function works to balance the agonism of adrenergic (sympathomimetic!) receptors, thus allowing our body to essentially work “normally”.  So if you remember nothing else at all about muscarinic agonists (or “cholinergic drugs”), do remember the words REST and WET.  Now, to delve into more detail.  Woot!

There are 5 subtypes of muscarinic receptor, and they are all G Protein Coupled Receptors (if you don’t know what I’m talking about see “Our Friends the Receptors” in the basic pharmacology section).  Let’s make that easier and cut out the last two, because they are mostly in the CNS and the jury is still out on what exactly they do.  Actually, the jury is still out on almost every receptor type, but researchers have dedicated their work to studying them and make new discoveries every day!

Anyway, for our purposes there are 3 muscarinic subtypes: M1, M2, and M3.  I recommend remembering them as head, heart, and trunk.  While not entirely encompassing, it’s a start!

1.  M1:  Head.  These guys are in the CNS, on salivary glands, and surrounding your esophagus.  So they help regulate parasympathetic signals from the CNS, help to begin the digestive process (which starts with salivation!), signal the stomach to secrete digestive “juices”, and speed along signals to your organs.

2. M2:  Heart.  These are the important receptors that help regulate the conduction speed and contractile force of the atria in your heart.  They, too, are in the CNS and on the heart itself!  In the atria, they counter the effect of sympathetic stimulation by relaxing how hard those amazing atrial cardiomyocytes are pumping…Negative Inotropic! They also monitor signals from the CNS to ease up on the stimulation given to the AV node and slowing the conduction…Negative dromotropic!

3.  M3:  Trunk (and Eye…I know, this messes it up).  These guys are in the CNS, on the ciliary bodies in your eye (remember the little guys that control your pupil?), on your bronchioles, on your blood vessels, and all over your digestive system, from start to finish!  The most important thing to remember is that they help you digest by enhancing secretions from the salivary glands down to the colon.  Pretty amazing, huh?  In your lungs, they actually cause a bit of bronchoconstriction, which is why we have to be very careful using muscarinic agonists.  One of the coolest (IMHO) features of M3 receptors is how they affect the blood vessels.  I will nerd out on this in another post, so for now, just remember vasodilitation!  In the eyes, they cause myosis, or pupillary constriction.

Can you guess what the opthamologist drops in your eyes to make your pupils HUGE?

So there you go.  Secretions and rest (mostly). Here is a summary of what muscarinic receptors are in charge of:

1.  Secretions along the digestive tract

2. Reduced contractility and conduction of the atria

3. Vasodilitation

4. Myosis

5. Speeding along autonomic signals

6. Bronchoconstriction

There was a lot of information in this post!  I needed help too (one can only pack so much into the Rolodex), so I consulted the humongous bag of notes I have.  These notes came from two lecturers:

Robert Mouton at Concordia University, Austin, TX.  He is a cell biologist and incredible professor of pharmacology and physiology.

Dr. Sue Greenfield at Columbia University, New York, NY.  She is a nurse practitioner and PhD who has a vast clinical knowledge of drugs and has the amazing ability to put their use into simple terms!

*But…why didn’t we talk about sweat??  Well, as I was writing this, I realized that the simplest way to remember muscarinic drugs is by their parasympathetic activity.  So…diaphoresis is indeed a muscarinic activity, but it is modulated by the sympathetic nervous system.  I know, I know!!  It’s very complicated.  If I were you, I’d just remember that most things wet come from M receptors.

**But…why didn’t we talk about tears??  Lacrimation is one of those tricky things that happen via the CNS, more specifically the cranial nerves.  The “tear signal” from that good old cranial nerve VII is modulated by muscarinic receptors.  Again, don’t cry over it.  Just assume that wet is muscarinic and if you are very curious then look it up!

So I sacrificed complete accuracy for a good title.

Mu and Kappa Receptors: Blame it on the Pain

If you remember anything at all about receptors for opiates (morphine) and opioids (drugs that act like morphine), remember the Mu (myoo) Receptor.  It’s the main go-to receptor for pain relief in the body.  There are also Kappa Receptors.  They too are involved in pain relief, but to a lesser extent.

You will learn what you need to know about opioid analgesics when you study the drugs.  But just in case you are curious about the receptor…

First of all, you don’t need morphine or any other drug to activate the Mu and Kappa receptors.  They are naturally activated by three endogenous hormones:  enkalphalins, endorphins, and dynorphins.  Your body really needs this feature, because if you ever, say, cut off a fingertip while chopping onions, you want a little analgesia for the first few seconds before you actually look. The involvement of your psyche is another story for another time.

So morphine is the prototype, or typical example, of a Mu receptor agonist.  We call this class of drugs opioid analgesics (morphine-related pain relievers).  More on the specifics later.  Some things you should be aware of regarding Mu receptors:

1) They are located in the central nervous system (mostly in the spinal column)

2) Their activation relieves pain, produces euphoria, and also DEPRESSES the CNS

3) CNS depression affects the control centers in the brain stem (remember those?).  So it lowers your blood pressure and heart rate, but most important to remember is that is lowers your respiratory rate.  It also may lower your level of consciousness.

4) The receptors love their agonists.  So when an opioid attaches to a mu receptor over the course of time (chronic abuse or even chronic therapeutic use), the neurons they are attached to build more receptors and more mechanisms for processing the signals sent by them!  This is part of a chain of events that causes the infamous opiate addiction.