Cholinergic receptors

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Introduction0:00–0:21

Cholinergic receptors are receptors on the surface of cells that get activated when they bind a type of neurotransmitter called acetylcholine.
There are two types of cholinergic receptors, called nicotinic and muscarinic receptors - named after the drugs that work on them.

Nervous system0:21–2:13

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 is divided into the somatic nervous system, which controls skeletal muscles, and the autonomic nervous system, which is further divided into the sympathetic and the parasympathetic, and controls internal organs.
Neurons are the main cells of the nervous system. They’re composed of a cell body, which contains all the organelles, and nerve fibers, which are projections that extend out from the neuron cell body.
Nerve fibers are dendrites that receive signals from other neurons, and axons that send signals along to other neurons. Where two neurons come together is called a synapse; that’s where 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 sympathetic and parasympathetic - 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 out of the spinal cord.
Axons of preganglionic neurons exit the spinal cord to reach the ganglia and synapse with postganglionic neurons. Then, the axons of postganglionic neurons exit the ganglia to reach the organs and synapse with the target organ cells.

Sympathetic synapses2:13–4:03

Let’s zoom into the synapses. In the sympathetic nervous system, preganglionic and postganglionic neurons release different neurotransmitters.
Preganglionic neurons release the neurotransmitter acetylcholine, which binds to nicotinic receptors on the cell membrane of postganglionic neuron cell bodies.
And most postganglionic neurons release the neurotransmitters adrenaline and noradrenaline, collectively called catecholamines.
These catecholamines bind to adrenergic receptors on the plasma membrane of the target organ cells. A few sympathetic postganglionic neurons release acetylcholine, which binds to muscarinic receptors on target organ cells.
Now for the parasympathetic nervous system, both preganglionic and postganglionic neurons release acetylcholine. The acetylcholine released by preganglionic neurons binds to nicotinic receptors on postganglionic neuron cell bodies.
Then, the postganglionic neurons release acetylcholine, but in this case it binds to the muscarinic receptors on the target organ cells.
In the somatic nervous system, the site where a motor neuron axon comes into contact with a skeletal muscle fiber is called a neuromuscular junction.
Whenever a motor neuron receives an electrical impulse from the brain, this triggers the release of small vesicles that contain acetylcholine into the neuromuscular junction.
Acetylcholine then binds to the nicotinic receptors on skeletal muscle cells, and triggers skeletal muscle contraction. Now, nicotinic receptors are also called ionotropic acetylcholine receptors, because they are ligand gated ion channels, which means that they open when acetylcholine binds, allowing positively charged ions like sodium and potassium to flow through them.

Nicotinic receptors4:03–4:56

Nicotinic receptors are made of five subunits, two alpha, one beta, one gamma, and one delta subunit, and together they form a tunnel that’s generally closed.
When acetylcholine binds to the alpha subunits, the tunnel changes shape and opens up. That lets sodium flow into the cell, and potassium out of the cell, following a passive gradient.
This leads to depolarization of the cell, which is when the cell undergoes a shift in electric charge distribution and becomes more positive, triggering a cellular response.

Muscarinic receptors4:56–7:36

Muscarinic receptors are also known as metabotropic acetylcholine receptors because they activate intracellular proteins when acetylcholine binds.
Muscarinic receptors are seven pass transmembrane receptors, which means they are really long proteins that have one end that sits outside the cell and binds acetylcholine, 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 within the cell activates intracellular proteins. Muscarinic 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 guanosine diphosphate or GDP when they’re inactive, and to guanosine triphosphate or GTP 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 keep the G protein right next to the muscarinic receptor.
When the alpha subunit is bound to GDP, the three subunits stay together, so this flower is closed. But when the alpha subunit is bound to GTP, the alpha subunit separates from the beta and gamma subunits, like one petal opening and separating from the others, so the alpha subunit is free to interact with other proteins, stimulating some while inhibiting others.
To act on other proteins, the alpha subunit 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.
There are three types of G proteins: Gq, Gi, and Gs, and each one stimulates and inhibits a different set of molecular pathways.
Now, there are five main groups of muscarinic receptors - M1, M2, M3, M4, and M5 - and they’re grouped by the G protein they’re coupled with.
So M1, M3, and M5 receptors are coupled with Gq proteins, and M1 is also coupled to a small extent with Gi and Gs, while M2 and M4 receptors are coupled with Gi proteins.
The key is that the cells of each target organ may have one or more of these receptors. Now when M1, M3 or M5 receptors bind acetylcholine, the receptor changes its shape and this allows the Gq protein to release GDP and bind GTP instead, activating it.

M1, M3, M5 receptors7:36–10:21

The active Gq protein then activates the enzyme phospholipase C, which is found in the cell membrane. Phospholipase C then cleaves a phospholipid called phosphatidylinositol 4,5-bisphosphate into two, one part is inositol trisphosphate, which is soluble and diffuses freely in the cytoplasm, and the other part is diacylglycerol, which remains attached to the cell membrane.
Inositol trisphosphate travels through the cytoplasm and gets to the endoplasmic reticulum membrane where it opens up calcium channels.
Since calcium concentration is higher in the endoplasmic reticulum than in the cytoplasm, calcium flows out of the endoplasmic reticulum to the cytoplasm.
The increased calcium concentration in the cytoplasm changes the electrical charge in the cell and it can lead to depolarization.
In the meantime, diacylglycerol binds the enzyme protein kinase C, but to be fully activated, protein kinase C also needs calcium.
Once calcium levels in the cell go up, protein kinase C starts to phosphorylate other target proteins. In other words protein kinase C goes around adding phosphoryl groups to target proteins and that activates them, triggering a cellular response that differs from cell to cell.
M1 receptors may also be coupled with the protein Gs, which stimulates an enzyme 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 binds to the regulatory subunit of the enzyme protein kinase A, and this 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 after dissociating, the catalytic subunit of protein kinase A is free to phosphorylate target proteins that trigger a cellular response.

M2, M4 receptors10:21–10:55

Finally, M2, M4, and to a small extent M1 receptors are 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 rest and digest parasympathetic response, like slowing the heart rate and keeping the body energy use as low as possible to help digestion.

Review10:55–11:41

Alright, as a quick recap, there are two groups of cholinergic receptors. Nicotinic receptors are ligand gated ion channels that allow sodium and potassium to flow through them, causing cell depolarization.
Muscarinic receptors are G-protein coupled receptors. M1, M3 and M5 interact with Gq, which triggers a cascade that ultimately activates the enzyme PKC.
M1 interacts to a small extent with Gs, which stimulates adenylate cyclase to increase cAMP and activate PKA. And M2, M4, and to a small extent M1 interact with Gi, which inhibits adenylate cyclase causes a negative feedback on the effect of the protein Gs.