G-Protein & G-Protein-Coupled Receptors (GPCR) | Cell Surface Receptor | Physiology | Endocrinology

what's up lovely people this is mitochosis perfectionist where medicine makes perfect sense let's resume our endocrinology playlist we are in the topic of cell signal transduction today we'll focus on a cell surface receptor and the story of the g protein so let's get started this is my endocrinology playlist watch these videos in order especially the last two if you don't understand this one here's a very important fact to keep in your mind almost all of the active particles in your body are proteins all channels are proteins all pumps are proteins all carriers are proteins all

enzymes are proteins or receptors are proteins anything that's going to be switched on switched off rotate have a conformational change anything of this sort is going to be a protein for a very simple reason go back to biochemistry and molecular biology and remember the story of dna synthesis transcription and translation and then you have post-translational modification remember the primary structure of protein secondary structure tertiary structures proteins are complex indeed however hormones beg to differ they could be proteins or fat if they are proteins they are water soluble if they are fat of course they are

water insoluble but lipid soluble i don't just mean proteins i mean proteins peptides polypeptides amy and the entire family as we have said gazillion times before there is a ceo followed by a general manager and then you have employees and independent contractors only three glands listen to the pituitary these three glands who listen to the pituitary produce steroidal hormones that are fat soluble and that's why they are slower in action contrast that with the independent contractors they produce peptides proteins and therefore they are faster why are lipid soluble hormones slow in action because you have

to leave the plasma protein and then go until you reach the cell membrane the cell membrane is lipid and the hormone is lipid lipid can diffuse through lipid but this process is very slow i have to diffuse throughout the cell membrane and then go through the cytoplasm and then reach the receptor maybe in the cytoplasm or the nucleus this is a very slow process and wait there is more i then have to tap on the dna knock on the door hey dna would you like to like replicate and transcription translation make me some brand new

proteins oh yeah sure all of this takes time conversely if your water soluble hormone you just cannot pass through the membrane because the membrane is lipid and you are water soluble therefore you have to stay outside and then latch onto a cell surface receptor and this is like flipping a switch on and just like your bedroom when you turn on the lights you just click on the switch and boom the light is on it's a very fast process if the hormone is lipid soluble we put the receptor inside because you can diffuse through the membrane

but if the hormone is water soluble we have to put the receptor outside a soil surface receptor because the hormone cannot enter through the lipid bilayer membrane these receptors especially those coupled to a g protein are integral proteins because they take the whole thickness of the membrane if you wanna remember the difference between integral proteins and peripheral proteins go back to my physiology playlist and check the video titled the functions of protein in the cell membrane the distinction between lipid soluble hormones and water-soluble hormones was discussed before just remember today's topic is the g protein

we are talking about water soluble because the receptor has to be on the outside who's gonna link the receptor on the outside with the enzyme on the inside that's the purpose of the g-protein what are these water-soluble hormones there are many including the pituitary hormones pancreatic hormones parathyroid hormones and your catecholamines which include epinephrine norepinephrine and dopamine if you are a lipid-soluble hormone which is not today's topic you just diffuse through the cell membrane which is made of lipid until you reach your receptor which is usually in the cytoplasm or the nucleus then we have

a ligand receptor complex which will activate hormone response elements which will activate dna first replication when you convert dna to dna or transcription which is dna to rna or translation from rna to proteins all of this takes a very long time these are slow acting examples of these fat soluble hormones you have all of the steroidal hormones these include the hormones secreted by your adrenal cortex zona glomerulosa zona fasciculata zona reticularis and then add the testicles testosterone ovaries estrogens and progesterone moreover there are the thyroid hormones t3 and t4 as well as vitamin d all

of these are lipid soluble that's not today's topic today's topic is the water soluble hormones can you diffuse to the membrane that's made of lipid nope i cannot so therefore you have to put the receptor on the outside all right the receptors on the outside the enzyme the actual action is on the inside who is the middle man that's gonna connect the receptor on the outside with the enzyme on the inside this is the story of the g protein it's the middle main why do you call it g protein why not f as in fme

because this is the guanine nucleotide binding proteins it can bind to gtp or gdp that's why we call the g protein so here is your lovely water soluble hormone it's going to act on a cell surface receptor of course all receptors are proteins when this happens you got the ligand receptor complex which is active this will activate the g protein the g protein will then activate the enzymes known as second messenger systems who's the first messenger the water soluble hormone who's the second messenger you have many choices that's the action do you remember this beautiful

chart yes we are done with the intracellular receptors these are the steroidal hormones thyroid hormones vitamin d boom we're done we're talking today about what g protein coupled receptors which are the most important cell surface receptors when the hormone is water soluble or hydrophilic the receptor has to be on the cell surface we have three types g-protein-coupled receptor by far the largest and the most significant family ligand-gated ion channels and enzyme-length receptors now let's talk about the g-protein-coupled receptor g-protein-coupled receptors the largest family of cell surface receptors no kidding the action of those g protein

coupled receptors depend on three factors number one the receptor number two the g protein itself number three the effector molecules the second messenger systems the actual freaking action tell me about this ligand oh right this ligand is a hydrophilic hormone something that's water soluble thank you can you give me example of these water soluble molecules sure it could be catecholamine such as epinephrine norepinephrine dopamine say thank you to your adrenal medulla could be acetylcholine oh yeah you see sympathetic and parasympathetic awesome glucagon to raise your blood sugar serotonin to make your brain happy secretin a

hormone that secretes and pituitary hormones such as tsh acth fsh and lh tsh is stimulating the thyroid gland acta stimulating the adrenal cortex fsh and lh are submitting the gonads thyroid gland adrenal cortex gonads these are the three employees the three glands that obey the pituitary but homo medicosis haven't you said that the three glands that obey the pituitary secrete lipid-soluble hormones that's true the glands themselves secrete lipid-soluble hormones but these glands get stimulated by pituitary hormones that are water-soluble big difference so tsh acth fs8 and lh are water soluble however thyroid hormone t3 and

t4 cortisol aldosterone testosterone estrogens and progesterone these are lipid soluble we're done with the ligand tell me about the receptor this receptor has seven trans membrane helices you know a helix yeah you have seven of these making the receptor a very complex three-dimensional structure but just let's keep it simple and we'll do seven healthy right there look at this one two three four five six seven talk to me about the outer surface of the or the outer region of the receptor well the outer part is extra extracellular no kidding and it's the binding site of

the ligand which is a water-soluble molecule thank you tell me about the inner surface the inner surface of the receptor is intracellular of course is the binding site of the g-protein thank you and after the g protein what do we got here the effector molecules which are three gq gs or gi so we have seven transmembrane helices and three intracellular effector molecules they are intracellular but they are still bound to the inner surface of the cell membrane okay mitochosis now i know about the ligand now i know about the receptor tell me about the g

protein your wish is my command the g protein g4 guanine nucleotide binding protein what do you mean by guanine nucleotide i mean either gtp or gdb this g protein will bind gdb when the g protein is inactive but when the g protein gets activated it's gonna bind to the gtp because it has an extra phosphate group how can the gdp become gtp just acquire a phosphate group but how will the gtp become gdp destroy a phosphate group break down a phosphate from it how do i break it down hydrolysis what's the name of the enzyme

gt phase which broke down the gtp when you convert gtp into gdp this is converting the active g protein into an inactive g protein and that's why gt pays terminates the activity of the g protein all right let me tell you about this g protein has a trimeric protein structure three subunits alpha subunit which is the story beta subunit and gamma subunit and the story of the g protein looks like this the g protein was inactive which means bound to gdp suddenly it decided to become active how did it decide well a soluble particle came

and bound to the receptor now the g protein is active when it's active it's gonna ditch that gdp and it's gonna bind gtp gtp will activate the alpha subunit when the alpha subunit gets active it will kick the beta and the gamma subunit away from it and the alpha will remain alone alone in an active form who will end the alpha subunit's entire career gt pays because it breaks down the gtp into gdp what's the function of the beta subunit it just forms a complex with the gamma subunit what's the function of the gamma subunit

it forms a complex with the beta subunit this structure is anchored to the cell membrane via a lipid anchor because the cell membrane is made of lipid activation of the g protein first this water soluble hydrophilic extracellular ligand is going to bind to the receptor thank you the receptor will undergo a conformational change its three-dimensional structure is gonna change in shape this activated receptor is gonna bind to the g protein which is an intracellular structure when g proteins becomes active it's gonna bind gtp instead of gdp when you're buying gtp when you are active alpha

subunit is gonna kick the beta and gamma complex in the teeth get away from me i am active eagles fly alone and when the alpha subunit is active it's going to activate the effector molecules gq gs or gi that's the story of activation who will end this activation process who will end the alpha subunit's career this is the gt phase because it breaks down gtp into gdp and phosphate i hope that you know that atp can be converted to click amp via adelaide cyclase enzyme you can take the cyclic emp to the cleaners by phosphodiesterase

enzyme which converts cyclic mp into inactive metabolites or degradation products or basically pieces of trash absolute rubbish who stimulates adenolate cyclase gs coupled receptor who inhibits adelaide cyclase gi coupled receptor s stands for stimulation i stands for inhibition no duh how can we inhibit the phosphodies trace enzyme by a phosphodiesterase inhibitor in other words there are two mechanisms by which you can increase the level of cyclic mp the first method is to boost the activity of adelaide cyclase by gs coupled receptor the second way to increase cyclic emp is to destroy the phosphodius trace so

that no one will take me to the cleaners so that the level of cyclic mp will rise so if you leave it to gs coupled receptors you will have more cyclic amp if you leave it to gi you will have less cyclic mp if you give a phosphodiesterase inhibitor you'll have more cyclic emp when you write cyclic amp make sure the c is lowercase because this has a completely different meaning you know the saying health books are the only books that can kill you because of a typo you should also grasp the fact that when

an enzyme is called kinase it's usually gonna add a phosphate but when the enzyme is called phosphatase it's gonna remove a phosphate let's do it again the water soluble hormone is now bound to the receptor protein and then when this is active i can activate the g protein alpha will fly alone beta and gamma will make a complex and get out of here alpha is active to do what to activate gs gq or gi when the g protein was inactive it was like this bound to gdp and these three were together but look at here

look when it's active when it's active different things will happen but first of all who activated the g-protein the binding of the water-soluble hormone to the receptor a conformational change will happen to this receptor now the g-protein is active and it's going to bind gtp instead of gdp the alpha subunit is now active and it's going to kick the beta gamma complex in the teeth get out of here alpha subunit is active to do what to activate gq gs or gi depending on the situation gq will do what when you activate gq you'll activate phospholipase

c which will increase calcium gq calcium also think of gq magazine very muscular dudes when you activate gs it will activate at a late cyclase more cyclic emp when you activate gi it's going to inhibit adelaide cyclase less cyclic amp when i am inactive i am bound to gdp who did this the jt pays gt pays destroyed the gtp and now you have gdp when you're buying gdp you are inactive and you are inactive because the water soluble hormone is detached but when you are active the water soluble hormone is attached and the gdp is

becoming gtp by acquiring an extra phosphate group pause and review if you have watched the last video what did we say we said that alpha 1 m1 m3 m5 h1 v1 and others are gq coupled gq meaning phospholipase c and therefore calcium contraction of smooth muscles vasoconstriction bronchoconstriction uterine contractions all kinds of smooth muscle contraction that's why oxytocin is gq coupled because it increases uterine wall contraction and the uterus has smooth muscles that's why angiotensin ii is gq coupled because it causes vasoconstriction of blood vessels again contraction of smooth muscles that's why the v1 receptor

of adh is gq coupled because it causes vasoconstriction how about the gs coupled receptors remember your sympathetic stuff especially the betas beta 1 beta 2 beta 3 because the alpha is here alpha 1 is gq coupled alpha 2 is gi because it's inhibitory alpha 2 is an sob alpha 2 is anti-sympathetic but the betas all of them are gs coupled therefore activate adelaide cyclase converts atp into cyclic mp activates protein kinase a everything here is a adelaide cyclase atp cyclic amp protein kinase a to do what increase the contraction of the heart increase cardiac contractility

and vasodilation so i relax smooth muscles unlike the calcium story phospholipase contracts smooth muscles but protein kinase a relaxes smooth muscles bronchodilation vasodilation what's the opposite of uterine contractions it's called tocolysis which is relaxation of uterine smooth muscles moreover beta 1 will increase renal secretion also increase aqueous humor secretion in the eye let's do the g protein story one more time a water soluble hormone is now bound to the receptor let's talk about gs make this about gs okay this is active right g protein when it's active is going to bind gtp alpha subunit is

going to dissociate from the beta gamma complex alpha alone will activate adelaide cyclase enzyme which converts atp into cyclic amp cyclic amp activates protein kinase a when i'm called a kinase what's the function i will add a phosphate this is the enzyme before the kinase this is the enzyme after the kinase it has acquired a phosphate and therefore became active most of the time here's the transporter before the protein kinase a but here's the transporter after protein kinase a protein kinase a adds a phosphate therefore the transporter is active most of the time receptor becomes

receptor phosphate transcription factor becomes transcription factor phosphate ion channel becomes ion channel phosphate structure protein structure protein phosphate i converted everything from inactive to active i am the protein kinase a but hey where did you get the phosphate group from easy i got it from the gtp that's why the active form of g protein always binds gtp and not gdp because i need this extra phosphate to activate all kinds of stuff all right how can we go from the active state back to the inactive state easy the cyclic mp is gonna be taken to the

cleaners thanks to phosphodiesterase enzyme and the protein kinase a will not be active instead you will activate a phosphatase what does a phosphatase do remove the phosphate the enzyme phosphate will go back to become an enzyme transporter phosphate will become a transporter and so and so forth basically converting the active form into the inactive form this was the story of the g protein it's a very simple concept it's just your work professor cannot teach do you remember the sympathetic nervous system yeah we had many sympathetic receptors including alpha-1 which is gq you know why because

it needs to constrict blood vessels calcium contraction of smooth muscles how about alpha 2 alpha 2 is anti-sympathetic because when you stimulate the alpha 2 it decreases norepinephrine it's anti-sympathetic when something inhibits its gi because i is inhibitory how about the betas the betas are gs because i need to relax the vessels relax the uterus but increase cardiac contractility i also need to secrete more renin and more icus humor let's talk about the muscarinic receptors of parasympathetic easy m1 m3 and m5 the odd numbers want to contract stuff contract smooth muscles and contract the asanas

of the gland to secrete stuff because this is secreto motor parasympathetic therefore when you want to contract smooth muscles you better be gq to increase the calcium but how about m2 and m4 i want to inhibit everything gi the odd numbers are gq the even numbers are gi the functions make perfect sense pause and review but hey medical says why is this so important take it easy my friend take it look at this sympathetic nervous system secretes norepinephrine right yeah i know this norepinephrine on the bladder what did it do it relaxes the wall and

constricts this fainter because i was running from a tiger relaxation and contraction are two different functions how come one ligand produces two opposite functions because the receptor is different and the g protein coupled receptor is different if you want to relax the wall of a smooth muscle you better be gs if you want to contract a smooth muscle you better be gq to increase the calcium it makes sense how about the parasympathetic nervous system is acetylcholine wants to calm the heart down how do i calm someone down gi is inhibitory that's why it's m2 it

has to be an even number i want to contract the walls of this bladder to get the urine out m3 gq coupled gq calcium contraction of smooth muscles i want to squeeze those gastric glands because i am secreto motor m3 is gq coupled gq calcium constriction what does your posterior pituitary gland release adh and oxytocin who synthesized these two hormones the prescription heck no it was the hypothalamus and we talked about why in previous videos in this endocrinology playlist what's the only function of adh to maintain your blood pressure to prevent your blood pressure from

dropping so let's say that you were walking down the street distracted with your phone and then you got hit by a car and lust lots of blood if we leave you alone you will die from hypotension but thankfully there is adh coming to try to save the day adh has one function in life to prevent your blood pressure from dropping to maintain a robust blood pressure let's go adh is gonna do this by two receptors v1 and v2 why v because it's a vasopressin vasopressin what do you think will do to the vessels of vasoconstriction

press them constrict them how do i do this v1 receptor will do this for you how about v2 v2 goes to the kidney and gets the water out reabsorbs the water so that the water goes back to the blood when we increase the amount of volume in your blood will increase the venous return and therefore increase the preload and increase the cardiac output and will increase the blood pressure preventing hypotension now take a wild guess if v1 wants to constrict vessels does it need gq gs or gi oh that's easy of course gq because gq

calcium contraction of smooth muscles how about dilating those beautiful collecting tubules and get the water out oh dilation relaxation of smooth muscles cyclic mp therefore gs coupled it's so easy tell me about dopamine there is d1 receptor and d2 d1 activates the direct pathway d1 dilates renal vessels mesenteric vessels as well d2 inhibits so when d1 activates do you think it's gs gq or gi and when g2 inhibits what kind of g-protein does it need well it has to be s for stimulation and i for inhibition also gs increases cyclic mp which dilates and relaxes

smooth muscles see medicine makes so much sense once you understand what the flip you're talking about it's so simple and easy there is no need to invent some woke mnemonics to remember these just think about it the best mnemonic is understanding histamine h1 wants to bronch a constrict h2 wants to increase gastric acid secretion and of course you cannot secrete without vasodilation because you get those secretions from the blood vessels and therefore h1 is gq coupled h2 is gs coupled to be continued in the next video don't forget i have a premium endocrine pharmacology course

on my website medicosisperfectionaries.com my website also has a renal physiology course we got all kinds of courses and for a limited time you can get a 40 discount towards anything on my website just use promo code kidney at checkout may your kidney always have a good threshold otherwise you will use your glucose in the urine thank you for watching please subscribe hit the bell and click on the join button you can support me here or here go to my website to download my courses be safe stay happy study hard this is medicos's perfect scenarios where

medicine makes perfect sense