Acetylcholine. ACh

okay we're going to talk about acetylcholine and answer the questions what is acetylcholine and what occurs during acetylcholine synthesis storage release receptor binding and degradation and what are some clinical correlations associated with acetylcholine hello everyone my name is dr morton and i'm the noted anatomist first question what is acetylcholine well it's a neurotransmitter derived from acetylcholae and choline so there's the chemical structure there's the acetyl group there's the choline group and xing they make a wonder twin power of acetylcholine and there's the ach abbreviation now many neurons release acetylcholine for example all parasympathetic neurons both preganglionic and postganglionic parasympathetic neurons release acetylcholine sympathetic neurons do but only the preganglionic not the postganglionic with the exception of sweat glands and then all somatic motor neurons release acetylcholine into the neuromuscular junction anywhere there's a skeletal muscle there's a neuron that releases acetylcholine to cause it to contract and then a variety of central nervous system neurons found in the basal forebrain the diencephalon the hippocampus and so forth basically all peripheral nervous system motor neurons release acetylcholine except postganglionic sympathetic neurons but even there is one exception the central nervous system neurons in these video tutorials are not ones that i'm going to focus on so much the following steps comprise the process of acetylcholine transmission and i'm going to talk about steps a through e using the following schematic so let's start with first the synthesis of acetylcholine acetylcholine is synthesized from acetyl coenzyme a and choline through an enzyme called choline acetyltransferase so here's a terminal axon and there's a mitochondria that gives rise through biochemical process to acetyl coa in the terminal axon membrane there is these high affinity choline transporters that take choline from the extracellular space and transport them into the cytoplasm of the neuron this is a rate limiting step of acetylcholine synthesis now to put those two together we have an enzyme called choline acetyl transferase that is has its highest concentrations in the nerve terminal and it's a marker that a neuron is cholinergic if you find this enzyme so choline acetyl transferase takes acetyl-coa and choline and xing puts them together to make acetylcholine choline acetyl transferase is like cupid or emma and then the acetylcholine transferase the choline acetyl transferase takes that acetylcholine and dumps it into the cytoplasm and so acetylchol acetylcholine i'm going to show as an orange circle or as that circle with a square on it in both ways in this tutorial there is the synthesis of acetylcholine next we're going to talk about a clinical correlate with a drug called hemicholinium which blocks the choline transporter if you block the choline transporter then choline cannot enter the neuron if that happens then choline acetyl transferase cannot synthesize the acetylcholine and therefore there's no ach to store and release all right let's now talk about the storage of acetylcholine ach is transported from the cytoplasm into a vesicle by a carrier protein called vesicular acetylcholine transporter so here's the terminal axon and all these acetylcholine molecules are wanting to get into these vesicles and so we have this vesicular acetylcholine transporter xing that takes acetylcholine from the cytoplasm and transports them or enables them to be transported into these individual vesicles like that so basically vacht loads the gumball machine if the gumballs are acetylcholine it puts them all together into a closed space there's about a thousand to fifty thousand acetylcholine molecules per vesicle so it doesn't look so much like this picture as it does that picture but then there's also three hundred thousand vesicles per cholinergic neuron so it doesn't look so much like that as it looks like that and so here in this uh e m the letter t represents an axon terminal terminal the letter m a skeletal muscle and those circles in the axon terminal are individual vesicles containing thousands of acetylcholine molecules now acetylcholine bound vesicles are protected by acetylcholine esterase which is an enzyme that cleaves acetylcholine into its acetate and choline counterparts but if you have acetylcholine inside the vesicles acetylcholine esterase cannot degrade them so there is the storage of acetylcholine now a clinical correlate there's a drug called vesamycol that blocks the vesicular acetylcholine transporter when that occurs it inhibits acetylcholine from being stored in a vesicle and these empty vesicles that have no ach then when the neuron goes to secrete them that vesicle fuses with the membrane and there's little to no release of acetylcholine let's now talk about the release of acetylcholine an action potential causes an influx of calcium and promotes vesicle fusion with the membrane and then ach is released into the synaptic cleft so here's a terminal axon and an action potential spreads over the terminal axon and then it causes this voltage-gated calcium channels to open and calcium influxes from a high to a low concentration into the cytoplasm and then the calcium interacts with the vesicles causing them to fuse with the presynaptic membrane with the by via these snare proteins and snare proteins mediate the fusion of the vesicles with the presynaptic membrane for release of acetylcholine into the synapse in other words you put nickels into the gumball machine to get gumballs out and so similarly you put calcium in to this terminal axon to get acetylcholine out unless you have a condition called lampert eaton myasthenics syndrome which is a rare autoimmune disorder where antibodies block and destroy voltage-gated calcium channels when this occurs calcium cannot enter into the cell and therefore calcium-dependent triggering synaptic vesicle does not occur and then as a result acetylcholine vesicles do not fuse with the membrane and the neuron does not release acetylcholine another clinical correlate is this botulinum toxin which cleaves the snare protein complex without the snare proteins the vesicles cannot fuse with the membrane and as a result neurons cannot release these vesicle-bound acetylcholine molecules and the botulinum toxin results in a disease called botulism which is the most poisonous biological substance known and it's latin for botulis which means sausage because it was called the sausage disease because pork sausage particularly is what people realize if you had bad pork sausage you get really really sick and a good chunk of people die now this this physician named uh justinis kerner was ahead of his time he was the first physician in germany and really recorded to describe the botul what we now know as botulism and he predicted that someday the substance causing the disease would have medical applications so the botulin and toxin in the early 70s was used they took a dilated version of the botulin and toxin and they treated strabismus so they would inject it into the lateral rectus in this case this patient has the lateral rectus is too tight and it paralyzes some of the strands of the lateral rectus to relax the eye to its natural position hyperhidrosis where people are sweating in the palms of their hands like crazy you inject the botulin and toxin it stops those neurons from secreting acetylcholine they stop sweating overactive bladder when they're always this urgency to urinate you put three or four of these injections of the botulin diluted botulin and toxin into the bladder and it relaxes the causes the bladder so it's not contracting and then cosmetically for wrinkles and also for migraine headaches is what the botulin and toxins use it's a beautiful example of human ingenuity this is why they call it the miracle toxin so there's the synthesis storage and release of acetylcholine let's now talk about cholinergic receptors so acetylcholine interacts with two main classifications of cholinergic receptors nicotinic and muscarinic squirrel i'm going to take a bit of a tangent here for a second so there's a tobacco plant that makes a molecule called nicotine and scientists realize that nicotine binds to receptors inside the body and they said hey guys what do we call this receptor that binds nicotine and they said i know let's call it nicotinic receptors then another group said hey there's this mushroom that creates a molecule called muscarin and musgrain binds to receptors inside the body and they said gentle people what do we call these receptors that bind muscarin they said i know we'll call them muscarinic receptors hence how we have nicotinic and muscarinic receptors something i want you to realize is that both nicotine and muscarine are not made in the body they're exogenous molecules but nicotinic and muscarinic receptors are made and found in the body so the pockets of the nicotinic and muscarinic receptors are specific to nicotine and muscarine respectively so nicotine cannot bind to muscarinic receptors and musgrin cannot bind into the pocket of a nicotinic receptor now enter acetylcholine acetylcholine is made and found inside the body and the structure of a needle of acetylcholine enables it to bind within the pockets of both the nicotinic receptors and muscarinic receptors so cholinergic receptors of nicotinic and muscarinic so the take home message is this acetylcholine binds to two types of cholinergic receptors nicotinic and muscarinic okay now the structure of acetylcholine is not really the shape of a circle in a square but i wanted to i drew it this way to show that it can bind to both of the pockets of the nicotinic and muscarinic receptors and that's the physiological and pharmacological thing i wanted you to recognize with acetylcholine now there are a couple of different types of nicotinic receptors there's nicotinic receptors found only on skeletal muscle hence the n little m for muscle and also found on postganglionic neuronal cell bodies hence the little n for neuron you can also find nicotinic receptors on the adrenal medulla chromophen cells these are ligand-gated ion channels now muscarinic receptor types there's three there's actually five but we'll focus on m1 in the cns m2 these receptors are primarily found in the heart and m3 which is found everywhere else in the body where parasympathetic innervation occurs plus sweat glands and muscarinic receptors function through a g-protein-coupled receptor where they use second messengers there are all the cholinergic receptors in the body let's now talk about the inactivation after acetylcholine performs its nerve signal transmitter function it is inactivated by acetylcholinesterase so here we have acetylcholinesterase which i have symbolized as a pair of scissors it's bound to the postsynaptic membrane adjacent the cholinergic receptors it's very efficient it cleaves acetylcholine molecules at a thousand per second and it's the primary way of inactivating acetylcholine it's the only neurotransmitter that is cleaved all the other neurotransmitters after they release by a neuron go through a process of reuptake like catecholamines so there are both the nicotinic and muscarinic cholinergic receptors and recognize they have the acetylcholinesterase enzyme beside it so when acetylcholine binds shing it breaks it off into the acetate and choline substrates or molecules and so that's what acetylcholine esterase does even unbound acetylcholine is broken down immediately as well even before it has a chance to bind to the receptor so acetylcholine released from the vesicles is more more in concentration and quantity than is what is actually needed for the physiological activity you have far more acetylcholine molecules than you have cholinergic receptors now a clinical correlate is you have these molecules called acetylcholinesterase inhibitors they inhibit acetylcholinesterase from breaking down acetylcholine when this occurs you have an increase of an accumulation of acetylcholine in the synapse thus prolonging the action of the stimulation examples of acetylcholinesterase inhibitors are organophosphates like fertilizers sarin gas horrible horrible effects on the body when you have a high concentration of acetylcholinesterase inhibitors and that my friends is acetylcholine in a nutshell [Music] [Music] [Music] you