Adrenergic receptors

Definitions & Key takeaways

Adrenergic receptors are proteins found on the surface of cells that respond to the hormone adrenaline (epinephrine). There are three types of adrenergic receptors - alpha, beta, and gamma. Each type responds to a different set of chemical signals from adrenalin.

When adrenaline binds to its receptor, it triggers a series of biochemical reactions inside the cell that result in increased heart rate, increased blood pressure, and other effects that prepare the body for physical activity.

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Introduction0:00–0:21

Adrenergic receptors are receptors on the surface of cells that get activated when they bind a type of neurotransmitter called a catecholamine.
Catecholamines are involved in the stimulation of our organs by the sympathetic nervous system; they help to trigger the fight or flight response.

Nervous system0:21–2:43

The nervous system is divided into the central nervous system, so the brain and spinal cord, and the peripheral nervous system, which includes all the nerves that connect the central nervous system to the muscles and organs.
The peripheral nervous system can be divided into the somatic nervous system, which controls voluntary movement of our skeletal muscles, and the autonomic nervous system, which is further divided into the sympathetic and the parasympathetic, and controls the involuntary movement of the smooth muscles and glands of our organs.
The sympathetic and parasympathetic nervous systems have opposite effects on the body. The sympathetic nervous system controls functions like increasing the heart rate and blood pressure, as well as slowing digestion.
All of this maximizes blood flow to the muscles and brain, and can help you either run away from a threat or fight it, which is why it’s also called the fight or flight response.
The parasympathetic nervous system instead slows the heart rate and stimulates digestion - the effects can be summarized as 'rest and digest'.
Now, neurons are the main cells of the nervous system. They’re composed of a cell body, which contains all the cell’s organelles, and nerve fibers, which are projections that extend out from the neuron cell body.
Nerve fibers are either dendrites that receive signals from other neurons, or axons that send signals along to other neurons.
Where two neurons come together is called a synapse, and that’s where one end of an axon releases neurotransmitters that bind to receptors present on the cell membrane of the dendrites or the cell body of the next neuron in the series.
Now the autonomic nervous system - so both the sympathetic and parasympathetic nervous system - is made up of a relay that includes two neurons: preganglionic neurons, which have their cell bodies in nuclei throughout the spinal cord, and postganglionic neurons, which have their cells bodies in ganglia outside of the spinal cord.
Axons of preganglionic neurons exit the spinal cord to reach the ganglia and synapse with the postganglionic neurons. Then, the axons of postganglionic neurons exit the ganglia to reach the organs and synapse with the target organ cells.

Sympathetic synapses2:43–3:18

Now let’s zoom into the synapses of the sympathetic nervous system. The preganglionic and postganglionic neurons release different neurotransmitters, which are the tiny molecules that nerve cells use to communicate with one another.
The preganglionic neurons release the neurotransmitter acetylcholine, which binds to nicotinic receptors on the cell membrane of postganglionic neuron cell bodies, activating them.
Then, most postganglionic neurons release the neurotransmitters adrenaline and noradrenaline, which are collectively called catecholamines.

Structure of adrenergic receptors3:18–6:14

Catecholamines bind and activate the adrenergic receptors that are located on the plasma membrane of the cells of the target organs.
Adrenergic receptors are seven-pass transmembrane receptors, which means they are really long proteins that have one end that sits outside the cell and binds catecholamines, and then the snake-like protein dips in and out of the cell membrane seven times, and finally ends on the inside of the cell.
The end of the protein that’s within the cell activates intracellular proteins. Adrenergic receptors are one type of G-protein coupled receptors or GPCRs, because they work directly with intracellular proteins called guanine nucleotide-binding proteins or G proteins, because they bind to a guanosine diphosphate or GDP molecule when they’re inactive, and to a guanosine triphosphate or GTP molecule when they’re active.
G proteins are made up of three subunits called alpha, beta, and gamma, sort of like a flower with three petals. The alpha and the gamma subunits are anchored to the cell membrane, and they allow the G protein to snuggle up right next to the adrenergic receptor.
When the alpha subunit is bound to guanosine diphosphate or GDP, the three subunits remain together, so this flower is closed.
However, when the alpha subunit is bound to guanosine triphosphate or GTP, the alpha subunit separates from the beta and gamma subunits, like one petal opening and separating from the others.
When the alpha subunit is unbound, it’s free to interact with other proteins, stimulating some while inhibiting others. To act on other proteins, the alpha subunit of the G protein has to consume the energy provided by the GTP molecule, turning it into GDP, and that’s how the G protein is turned off and the three subunits come together again.
Broadly speaking, there are three types of G proteins: Gq, Gi, and Gs, and each one stimulates and inhibits a different set of molecular pathways.
Now, going back to adrenergic receptors - there are two main groups - alpha and beta - with several subtypes, and they’re grouped by the G protein they’re coupled with.
So there’s an alpha1 adrenergic receptor coupled with a Gq protein, an alpha2 adrenergic receptor coupled with a Gi protein, and a beta1, beta2, and beta3 adrenergic receptor - all of which are coupled with Gs proteins.
Noradrenaline or norepinephrine bind and activate alpha1, alpha2, and beta1 receptors, whereas adrenaline or epinephrine can bind to all five of the alpha and beta receptors.
The key is that the cells of each target organ may have one or more of these receptors. Now when an alpha1 adrenergic receptor binds a catecholamine, the receptor changes its shape and this allows the Gq protein to release GDP and bind GTP instead, activating it.

Alpha-1 adrenergic receptors6:14–7:58

The active Gq protein then activates the enzyme phospholipase C (PLC), which is found in the cell membrane. PLC then cleaves a phospholipid called phosphatidylinositol 4,5-bisphosphate (PIP2) into two, one part is inositol trisphosphate (IP3), which is soluble and diffuses freely in the cytoplasm, and the other part is diacylglycerol (DAG), which remains attached to the cell membrane.
IP3 travels through the cytoplasm and gets to the endoplasmic reticulum membrane where it opens up calcium channels. Since the calcium concentration is higher in the endoplasmic reticulum than in the cytoplasm, calcium flows out of the endoplasmic reticulum into the cytoplasm.
The increased calcium concentration in the cytoplasm can cause the electrical charge in the cell to change and it can lead to cell depolarization.
In the meantime, DAG binds the enzyme protein kinase C (PKC), but to be fully activated, PKC also needs calcium. Once calcium levels in the cell go up, PKC starts to phosphorylate other target proteins.
In other words PKC goes around adding phosphoryl groups to target proteins and that activates them, triggering a cellular response which differs from cell to cell.

Beta adrenergic receptors7:58–9:08

Now when all three of the beta adrenergic receptors binds a catecholamine, the receptor also changes its shape, but this time, the beta receptors are coupled to the protein Gs, which stimulates an enzyme that is known as adenylate cyclase.
Activated adenylate cyclase takes adenosine triphosphate or ATP, and removes two phosphate molecules transforming it into cyclic adenosine monophosphate or cAMP.
cAMP then moves throughout the cytoplasm and it binds to the regulatory subunit of the enzyme protein kinase A (PKA). When it binds to this part of PKA, cAMP makes it dissociate from the rest of the protein which is the catalytic subunit of protein kinase A.
It’s like pulling the pin out of the fire extinguisher - it allows the fire extinguisher to do its job. So when there’s a lot of cAMP around, the catalytic subunit of protein kinase A is free to phosphorylate target proteins that trigger a cellular response.

Alpha-2 adrenergic receptors9:08–9:42

Finally, when alpha2 adrenergic receptors bind a catecholamine, the receptor changes its shape, but in this case, the receptor is coupled to the protein Gi, which is also bound to adenylate cyclase - but in this case, inhibits it.
This causes a negative feedback on the effect of the protein Gs. This is particularly important in helping to inactivate cells in organs that are less important during the fight or flight sympathetic response, like the gastrointestinal tract and the bladder.

Review9:42–10:20

Alright, as a quick recap, adrenergic receptors are G-protein coupled receptors present on the cell membrane of many organs.
Alpha1 receptor interacts with Gq, which triggers a cascade that ultimately activates the enzyme PKC. Beta receptors interact with Gs, which stimulates adenylate cyclase to increase cAMP and activate PKA.
And alpha2 receptors interact with Gi, which inhibits adenylate cyclase causes a negative feedback on the effect of the protein Gs.