Signal Transduction Pathways (G-Protein, Receptor Tyrosine Kinase, cGMP)

Summary

In this educational video, the presenter dives into the complex world of signal transduction, a crucial topic in biochemistry and immunology. They discuss the importance of understanding G-protein coupled receptors, detailing their role in clinical applications and their impact on various bodily systems. The video simplifies the process of signal binding, G protein activation, and the subsequent activation of secondary messengers like cAMP, calcium, and protein kinases. Mnemonics are provided to aid memorization, and the discussion touches on the influence of this pathway on endocrine hormones. The video is designed to help viewers grasp this high-yield topic for medical exams, emphasizing the significance of not overlooking such fundamental concepts.

Takeaways

• 📚 Signal transduction is a crucial topic in biochemistry and immunology, affecting various aspects of human physiology.
• 🔗 G-protein-coupled receptors (GPCRs) play a significant role in signal transduction, with their activation leading to various cellular responses.
• 🔑 The GPCR pathway involves a G protein network that, upon signal binding, leads to conformational changes and activation of the alpha subunit.
• 🎯 G proteins can stimulate or inhibit adenylyl cyclase, which in turn affects the production of cAMP and the activation of protein kinase A (PKA).
• 🌟 The alpha subunit of G proteins can also work through Gq, leading to the activation of phospholipase C, which converts PIP2 into IP3 and DAG, influencing calcium release and protein kinase C (PKC) activation.
• 🧠 The mnemonic 'AC for Craps and Poker' is suggested to remember the GPCR pathway, associating 'AC' with adenylyl cyclase, 'C' with cAMP, and 'P' with PKA.
• 💉 Hormones like FSH, LH, ACTH, TSH, and others are under the control of the cAMP pathway, which is part of the GPCR signaling.
• 🔬 Receptor tyrosine kinases (RTKs) are a large class of signal transducers with inherent enzyme activity, involved in processes like dimerization and cross-phosphorylation.
• 🌐 The RTK pathway involves a complex cascade of kinases, including ROS, RAF, MEK, and ERK, leading to the regulation of transcription products.
• 🏥 The cGMP pathway, initiated by nitric oxide, involves guanylate cyclase and protein kinase G, and is associated with smooth muscle effects like vasodilation.

Q & A

What is the main topic of the video?

The main topic of the video is signal transduction, a major concept in biochemistry and immunology.

Why is signal transduction considered important in medical studies?

Signal transduction is important because it is clinically significant, influencing biochemistry, endocrinology, neurology, and psychiatry, and is a high-yield topic for medical exams.

What is a G-protein-coupled receptor and how does it function?

A G-protein-coupled receptor is a type of cell membrane receptor that, when a signal binds to it, triggers a conformational change in an associated G protein, leading to signal transduction.

What are the three subunits of a heterotrimeric G protein?

The three subunits of a heterotrimeric G protein are the alpha, beta, and gamma subunits.

How does the G protein network respond when a signal binds to the receptor?

When a signal binds to the receptor, the G protein network undergoes a conformational change, leading to the dissociation of the alpha subunit and the conversion of GDP to GTP, activating the alpha subunit.

What is the role of adenylyl cyclase in signal transduction?

Adenylyl cyclase converts ATP into cAMP, which then activates protein kinase A (PKA), leading to further downstream secondary messenger effects.

What are the different pathways that can be activated by the alpha subunit of a G protein?

The alpha subunit can activate adenylyl cyclase (Gs), inhibit adenylyl cyclase (Gi), or work through a different system involving Gq and phospholipase C.

What are the downstream effects of the IP3 and DAG produced by phospholipase C?

IP3 causes the release of calcium from the endoplasmic reticulum, and DAG activates protein kinase C (PKC), both leading to further downstream effects.

What is the mnemonic provided in the video to remember the G protein pathway?

The mnemonic provided is 'AC for Craps and Poker', which stands for Adenylyl Cyclase, cAMP, and Protein Kinase A.

What are the types of endocrine hormones controlled by the cAMP pathway?

The cAMP pathway controls endocrine hormones such as FSH, LH, ACTH, TSH, CRH, HCG, ADH, MSH, PTH, Calcitonin, GHRH, Glucagon, and Histamine (H2 receptor).

How do receptor tyrosine kinases differ from G-protein-coupled receptors?

Receptor tyrosine kinases have inherent enzyme activity and undergo dimerization and cross-phosphorylation upon binding of growth factors or signaling molecules.

What is the significance of the Ras-Raf-MEK-ERK pathway in signal transduction?

The Ras-Raf-MEK-ERK pathway is significant as it amplifies the initial signal through a series of kinase activations, leading to regulation of various transcription products and cellular responses.

What is the role of nitric oxide in the cGMP pathway?

Nitric oxide activates guanylate cyclase, which converts GTP into cGMP, leading to the activation of protein kinase G and effects on smooth muscles.

What mnemonic is provided for remembering the receptor tyrosine kinase pathway?

The mnemonic is 'RTK', which stands for Receptor Tyrosine Kinase, Ross, and three kinases (MAP kinase cascade).

Outlines

00:00

📚 Introduction to Signal Transduction

The speaker introduces the topic of signal transduction, acknowledging its complexity and importance in various medical fields. They encourage viewers to support the channel by joining as a 'Dirty Medicine' member for a monthly fee, which provides access to exclusive content and the ability to influence future video topics. The speaker emphasizes the clinical significance of understanding signal transduction, particularly the second messenger system, and its relevance to biochemistry, endocrinology, neurology, and psychiatry. They promise to provide a comprehensive understanding of the topic to help viewers excel in exams.

05:01

🔬 G-Protein Coupled Receptors and Signaling Pathways

This section delves into the workings of G-protein coupled receptors (GPCRs), explaining how signals bind to these receptors, leading to conformational changes and activation of the G protein's alpha subunit. The alpha subunit can either stimulate (through Gs) or inhibit (through Gi) adenylyl cyclase, which in turn affects the production of cAMP and the activation of protein kinase A (PKA). Alternatively, the alpha subunit can work through Gq, activating phospholipase C, which leads to the production of IP3 and DAG, influencing calcium release and protein kinase C (PKC) activation. The speaker provides a mnemonic to help remember this pathway and discusses the endocrine hormones affected by these signaling mechanisms.

10:01

🧬 Receptor Tyrosine Kinases and Their Signaling

The speaker discusses receptor tyrosine kinases (RTKs), which are unique because they possess inherent enzyme activity. They explain how growth factors or local signaling molecules bind to RTKs, leading to dimerization and cross-phosphorylation, which activates the receptors. This activation initiates a complex signaling cascade involving Ras, Raf, MEK, and ERK, which ultimately amplifies the initial signal and leads to the regulation of various transcription products. The speaker provides a mnemonic to remember the components of this pathway and highlights the endocrine hormones controlled by this mechanism.

15:02

🌐 The cGMP Pathway and Its Effects

The final section covers the cGMP pathway, which is introduced as the simplest to understand and memorize. The pathway begins with nitric oxide interacting with guanylate cyclase to produce cGMP, which then activates protein kinase G (PKG). This pathway has significant effects on smooth muscle function, particularly in vasodilation. The speaker summarizes the pathway as starting with nitric oxide and involving 'all the G's' (guanylate, cGMP, PKG), and notes that it controls the effects of BNP, ANP, and EDRF. The video concludes with a reminder of the high-yield nature of the information presented.

Keywords

💡Signal Transduction

Signal transduction is a cellular process by which a cell converts one kind of signal or stimulus into another. In the video, it is described as a major topic in biochemistry and immunology, highlighting its clinical importance in controlling various human body functions. The script emphasizes the significance of understanding signal transduction for medical students, as it is involved in biochemistry, endocrinology, neurology, and psychiatry.

💡Second Messenger System

The second messenger system is a part of the signal transduction process that involves the use of intracellular molecules to transmit signals from cell surface receptors to the rest of the cell. The video script mentions that this system is crucial for understanding the communication within the human body and is a high-yield topic for medical exams.

💡G-Protein-Coupled Receptors (GPCRs)

G-Protein-Coupled Receptors are a large group of cell surface receptors that are involved in various physiological processes. In the script, they are described as having seven transmembrane domains and being associated with a G protein network. The video explains how signals bind to these receptors, leading to conformational changes and activation of the G protein, which then initiates various downstream effects.

💡G Protein

G proteins are a family of proteins that are involved in signal transduction. The video script describes them as heterotrimeric, meaning they consist of three subunits: alpha, beta, and gamma. The script explains how the binding of a signal to a GPCR can lead to the dissociation of the alpha subunit and the conversion of GDP to GTP, activating the G protein and initiating signal transduction.

💡Adenylyl Cyclase

Adenylyl cyclase is an enzyme that catalyzes the conversion of ATP to cAMP, which is a key step in signal transduction. In the video, it is mentioned as being activated by the alpha subunit of the G protein (Gs), leading to the production of cAMP and the subsequent activation of protein kinase A (PKA).

💡cAMP (Cyclic Adenosine Monophosphate)

cAMP is a second messenger that plays a crucial role in various cellular processes. The video script explains how it is produced by adenylyl cyclase and goes on to activate protein kinase A, which then has further downstream effects.

💡Protein Kinase A (PKA)

Protein kinase A is an enzyme that is activated by cAMP and plays a role in various cellular responses. The video script describes how it is activated by cAMP and then carries out secondary messenger effects, which are important for the cell's response to signals.

💡Phospholipase C

Phospholipase C is an enzyme that hydrolyzes phospholipids and is involved in signal transduction. In the video, it is mentioned as being activated by the alpha subunit of the G protein (Gq), leading to the production of IP3 and DAG, which have unique effects on the cell.

💡IP3 (Inositol Trisphosphate)

Inositol Trisphosphate is a second messenger that plays a role in the release of calcium from intracellular stores. The video script explains how it is produced by phospholipase C and causes the release of calcium from the endoplasmic reticulum, which then has further downstream effects.

💡DAG (Diacylglycerol)

Diacylglycerol is a second messenger that activates protein kinase C. In the video, it is mentioned as being produced by phospholipase C and leading to the activation of protein kinase C, which then carries out downstream effects.

💡Receptor Tyrosine Kinases

Receptor tyrosine kinases are a class of receptors that have inherent enzyme activity and play a role in signal transduction. The video script describes how they undergo dimerization and cross-phosphorylation when a growth factor binds to them, leading to the activation of various signaling pathways.

💡MAP Kinase Cascade

The MAP kinase cascade is a series of protein kinases that are involved in signal transduction. The video script explains how it is activated by receptor tyrosine kinases and leads to the phosphorylation of multiple substrates, amplifying the initial signal and leading to various cellular responses.

💡cGMP (Cyclic Guanosine Monophosphate)

cGMP is a second messenger that is involved in signal transduction, particularly in the regulation of smooth muscle function. The video script describes how it is produced by guanylate cyclase and goes on to activate protein kinase G, which has effects on smooth muscle cells.

Highlights

Introduction to the importance of signal transduction in biochemistry and immunology.

Explanation of the clinical significance of the second messenger system in the human body.

Discussion on the high yield nature of signal transduction for medical exams.

Overview of G-protein-coupled receptors and their role in signal transduction.

Description of the seven transmembrane domain structure of G-protein-coupled receptors.

Mechanism by which signals bind to receptors and initiate a conformational change in G proteins.

Function of Gs and Gi subunits in activating or inhibiting adenylyl cyclase.

Role of cAMP and protein kinase A (PKA) in signal transduction.

Mnemonic 'AC for Craps and Poker' to remember the G protein signaling pathway.

Differentiation between the roles of Gs, Gi, and Gq subunits in signal transduction.

Activation of phospholipase C by Gq and its downstream effects.

Release of calcium from the endoplasmic reticulum and activation of protein kinase C (PKC).

Summary of the big picture of G protein-coupled receptor signaling.

Types of endocrine hormones controlled by the cAMP and IP3 pathways.

Introduction to receptor tyrosine kinases and their inherent enzyme activity.

Process of dimerization and cross-phosphorylation in receptor tyrosine kinases.

Activation of Ras and the subsequent MAP kinase cascade in signal transduction.

Mnemonic for receptor tyrosine kinases: 'RTK' for Ross and three kinases.

Overview of the cGMP pathway and its simplicity compared to other pathways.

Role of nitric oxide in the cGMP pathway and its effects on smooth muscles.

Endocrine hormones controlled by the cGMP pathway, including BNP and EDRF.

Conclusion emphasizing the high yield and importance of understanding signal transduction for medical exams.

Transcripts

what is up dirty medicine subscribers

in today's video we are going to be

talking about signal

transduction

i know that's what you're all thinking

you're like damn it i hate this topic

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provide is so very much appreciated

but it doesn't matter if you don't

donate i'm still going to make the free

videos anyway

so in this video we are going to be

talking about

a major topic in biochemistry and

immunology

and this is signal transduction i cannot

stress enough

how high guild and important this topic

is for a couple reasons

one clinically the second messenger

system

is so important it literally has its

hand

in everything in the human body it

controls so much

of biochemistry and endocrinology

and neurology and neuroscience and

psychiatry it's literally in every topic

so clinically it's really important to

understand the foundation

of how all of that communication works

but then

as far as u.s emily or complex is

concerned it's a really high yield topic

i think that test writers know that

medical students just

cannot stand studying this they punt

this they chalk this up and figure you

know what

if i get a question i'm just gonna take

a guess and that's that

but no no no no you're not gonna do that

that is a defeatist attitude and here at

dirty medicine

i do not believe in giving up what

should be free points

so in this video i'm going to teach you

everything that you need to know

to get most if not all of your questions

correct

when it comes to signal transduction so

let's get started

by talking about g protein couple

receptors

so where do we begin well we've got a

plasma membrane which you see here

on the slide and embedded within that

plasma membrane

is a receptor and this is the

g-protein-coupled receptor

and if you look at the plasma membrane

here the receptor portion

has this seven transmembrane domain that

kind of goes in and out in and out and

it loops in and out from the intra and

extracellular side

now on the extracellular side you see

that little cup and that's where

our signal is going to bind but this is

the receptor

now the receptor is connected to or

associated with

a g protein network and that g protein

network is com

consists of three subunits hence the

name

heterotrimeric g protein it's a trimeric

tri meaning three three subunits so

we've got the gamma

alpha and beta subunit now how this

works is

the signal binds to the little cup of

the receptor which you see in the upper

left-hand

part of this slide and when that happens

you get a little bit of conformational

change within the trimeric protein

subunits

of the g protein so the gamma and the

beta subunit stay

up around the plasma membrane but that

alpha subunit

kind of dissociates a bit and i'm

oversimplifying this for the purposes of

explaining it it doesn't quite work like

this exactly in space

but on that alpha subunit you get the

conversion of gdp

to gtp and when the gtp

is on the alpha subunit of the g protein

you have a gtp bound alpha subunit

that's now

active now when the alpha subunit is

active

it can act in one of a few ways it can

be g

sub s or g sub i the g

sub s activates adenylyl cyclase

and adenylcyclase's role is to convert

atp

into c amp and then c

amp will activate protein kinase a

or pka and then pka will have further

downstream secondary messenger effects

so g

sub s activates adenylyl cyclase

which catalyzes the conversion from atp

to camp

and then camp goes on to activate

protein kinase a

so big picture here g proteins

alpha gs stimulates s for stimulates

adenylyl cyclase which turns on camp

which turns on pka

now gi i for inhibitory does the

opposite

it inhibits adenylyl cyclase which

never allows the conversion of atp to

see amp

which never allows pka to be activated

which never allows pka to go on and

carry out its secondary messenger

effects

so alpha subunit of the g protein can

either stimulate through gs

or inhibit through gi now there's

another

function that the alpha subunit can have

that's not gs

and that's not gi and instead of working

through a dental cyclase and then

camp and then pka it works through a

completely different system

so i'm going to show that on the right

hand side of this slide

so to be clear we're still talking about

a g protein coupled receptor

where the signal binds to the receptor

it induces the little bit of

conformational change

gdp still goes to gtp

you still get activation of the alpha

subunit of the g

protein and this is where we start to

get a little different here

so instead of stimulating through gs

or inhibiting through gi you're going to

get stimulatory action

but through gq and gq will go on

to activate phospholipase c

now phospholipase c will activate the

conversion of

pip 2 to ip3 plus

dag dag and it's ip3

and dag which each carry out unique

effects

so ip3 causes a release

of calcium from the endoplasmic

reticulum

and dag activates protein kinase c

or pkc now the combination of calcium

being released from the endoplasmic

reticulum

and protein kinase c being activated by

dag

will both have further downstream

effects particularly calcium

which will go on to activate a whole

host of enzymes

and carry out secondary messenger

functions

so on the right part of this slide the

big picture idea

is that alpha subunit of g protein works

through gq

which stimulates phospholipase c which

stimulates

pip2 into both ip3

and dag ip3 causes calcium release dag

activates protein kinase c

and then both calcium and pkc will go

on and carry out downstream secondary

messenger effects

so huge picture let's pause take one big

step back and look at this big picture

what's happening a g protein-coupled

receptor

can cause either the activation of

protein kinase a

the inhibition of protein kinase a

or the activation of both

calcium and protein kinase c

and depending on what the effect or the

intended effect is

through the secondary messenger system

protein kinase a

calcium and protein kinase c can go on

to have further intracellular control so

that's the big picture of what's going

on here

and now the question in your mind i can

hear it right now

dirty how do we remember this so here's

my mnemonic

again big picture g protein turns on a

dental cyclase

turns on camp which turns on pka

so my mnemonic is that you go to ac

for craps and poker so i know gambling

is legal in

a lot of areas now but back in the day

you really had to either go to las vegas

out in the west or atlantic city or ac

over on the east coast so you go to ac

for craps and poker

g for g protein ac for adenylyl cyclase

the c in craps is the c in camp and the

p

in poker is the p in pka so dumb

mnemonic

i get it but it's better than nothing

now

the only other thing that i need to

mention about this

g protein coupled receptor pathway

are the types of endocrine hormones that

are under the control

of the various elements of this

signaling pathway

so when it comes to the camp pathway

the endocrine hormones that are under

the influence of this pathway

is everything that you see on this slide

so we've got fsh

lh ac th tsh

crh hcg adh

and that's specific to the v2 receptor

msh

pth calcitonin ghrh

glucagon and then histamine and specific

to histamine we're talking about the h2

receptor so these are all of the

endocrine hormones under the control

of camp and then likewise we need to

talk about the endocrine hormones under

the control

of ip3 so this is working through the

other

part of the g-protein coupled receptor

pathway through gq phospholipase c

and then ip3 so ip3 controls

things that you see on this slide so

gnrh oxytocin

adh at the v1 receptor trh

histamine this time specific to the h1

receptor angiotensin ii and

gastrin so these are all under the

control of ip3

now let's switch gears and talk about

the next type of signal transduction

pathway

we're going to talk about receptor

tyrosine kinases

receptor tyrosine kinases are actually

the largest class of signal transductors

and these are very unique because

receptor tyrosine kinases

actually have inherent enzyme activity

so yes it's a receptor

but it also is technically an enzyme

hence the name

receptor tyrosine kinase now how does

this work

so growth factors or local signaling

molecules will bind

on top of the receptor tyrosine kinases

and when this happens it kind of forces

the two

components or the two receptor tyrosine

kinases

to move close to one again to one

another and link up also known

as dimerization so now we have the

formation

of a dimer and then the dimer undergoes

this really unique process

known as cross phosphorylation so pretty

much what's going on here is that there

is

the tyrosine kinase activity in each of

these dimers

cross phosphorylate each other so

they're they're literally

phosphorylating tyrosines on the other

receptor tyrosine kinase and this whole

process that you see here

with my little white lines showing you

that it's crossing

is known as cross-phosphorylation now

the result of this cross-phosphorylation

is that you get this thing called an sh2

domain and that's basically a binding

site

up on the top of the receptor tyrosine

kinase where

various enzymes and other molecules can

bind to

to kick off complex signal transduction

so let's take this one step further and

just imagine that you've got these

dimerized receptor tyrosine kinases

and they're sitting there just ready to

do their job

so along comes this ross

ras and typically ross is inactive

when it has gdp bound to it but once the

signaling molecule at the top of the

receptor

tyrosine kinase which is here shown in

light blue

binds you get dimerization you get cross

phosphorylation

ross binds to the sh2 domain and

then ross can become activated so the

way that that happens

is that the gdp gets exchanged for the

gtp and now you've got

activated ras and now ras will undergo

this complex pathway where it basically

will go to roth which will go to mech

which will go to irk

and it's not important that you

understand what each of these things

are doing but what is important is that

you understand that

as you go down through this pathway you

have

the presence of what's known as

activator and these are

serine threonine kinases in the map

kinase cascade and

basically what's happening here is

because all of these kinases are

activators and control

this pathway at each step of the way so

as you see here

map kinase kinase kinase controls raf

map kinase kinase controls mech and map

kinase

controls erc so pretty much as you go

down you just drop a kinase each time

but the big picture here is that because

each of these kinases

phosphorylate multiple substrates

as you go down that initial signal

pretty much gets amplified

so this leads to a very strong output at

the bottom of this transduction cascade

which can then go on to regulate lots of

different transcription products and

this will have pretty profound effects

as this moves throughout the

the cell so this is a very complex

pathway but for the purposes of usmle or

comlax really what you need to know

is that it is how the receptor tyrosine

kinase works back at the top so

dimerization cross phosphorylation

ross rough mech arc and as you go down

you have activators

map kinase kinase kinase and then just

drop one kinase as

you go down so that's kind of the big

picture with a lot of nitty-gritty

details

woven in in between and just like we

talked about with g-protein-coupled

receptors it's really

important to know the different

endocrine products which are controlled

by this pathway

so just to summarize as you see on this

slide receptor tyrosine kinases

control insulin igf-1 fgf

f and egf but dirty

how the hell will i remember the pathway

alright so my mnemonic here

is when you think of receptor tyrosine

kinase

think rtk receptor tyrosine kinase

rtk and rtk should remind you

ross iii kinases so what does this tell

you

all of this is kicked off by ross and

then three kinases

reminds you that the next thing after

ross

starts with map kinase kinase kinase and

then

three kinases as you go down just drop a

kinase

so rtk receptor tyrosine kinase r for

ross

t for three k for kinase and then if you

know that you're starting with the three

kinase map

after ross just drop a kinase as you go

down

simple done easy points so that's

receptor

tyrosine kinases the final signal

transduction pathway that we need to

talk about

and honestly it's the easiest one to

learn and to memorize so i saved it for

last so that you can end on a high note

and feel like you dominated this video

is the cgmp

pathway so the cgmp pathway is just

pretty simple so i'm just going to fly

through it

so you've got nitric oxide which

basically comes

inside of the membrane and interacts

with guanolate

cyclase guanolate cyclase converts

gtp into cgmp

and then cgmp goes on to activate

protein

kinase g the reason i think that this

pathway is just a little bit easier to

remember

and put all these things together into

this one box

is because pretty much everything in

this pathway with the exception of

nitric oxide

has the letter g so guanolate has g

c gmp has g protein kinase

g ends with g so this is all the g's

which get started by nitric

oxide now the endocrine hormones that

are controlled in this pathway are bnp

and and e-d-r-f and just as like a big

picture idea you just want to know that

the cgmp pathway has really profound

effects

on smooth muscles so this pathway has a

lot of effects on vasodilation

so for usmle and comlex just know that

nitric oxide kicks off all the g's so

guanolate c

g m p p k g and that it controls bnp and

p

and e d r f and that is it for this

video

i know it was a lot of nitty gritty

information but it's all very high yield

so make sure you know this information

well