Cell CommunicationCell Communication

AP BiologyAP Biology

Types of SignalingTypes of Signaling

Paracrine Paracrine – local – cell secretes a signal that – local – cell secretes a signal that binds to neighboring cell receptors binds to neighboring cell receptors (growth factors + attraction of immune cells)(growth factors + attraction of immune cells)

SynapticSynaptic – nerves produce neurotransmitters – nerves produce neurotransmitters that bind to receptors on an adjacent cellthat bind to receptors on an adjacent cell

HormoneHormone – chemical released into blood and – chemical released into blood and binds to receptors on distant cellsbinds to receptors on distant cells

Direct communicationDirect communication – diffusion of chemicals – diffusion of chemicals through plasmosdesmata or gap junctions through plasmosdesmata or gap junctions and direct contact in cell to cell recognition and direct contact in cell to cell recognition (immune cells)(immune cells)

Receptor Binding OutcomesReceptor Binding Outcomes

Signal binds to the receptor and Signal binds to the receptor and changes its shapechanges its shape

May cause receptors to aggregate and May cause receptors to aggregate and lead to endocytosislead to endocytosis

May open gated channelsMay open gated channels May turn on genes (growth factors and May turn on genes (growth factors and

steroid hormones)steroid hormones) sets off a series of chemical reactionssets off a series of chemical reactions May lead to cell division or cell deathMay lead to cell division or cell death Stimulate cell secretionStimulate cell secretion Changing cell shapeChanging cell shape Set off muscle contractionSet off muscle contraction

1 1 endocytosisendocytosis

2 opening a 2 opening a channelchannel

3 + 4 3 + 4 turning on a turning on a genegene

5 activate 5 activate enzymesenzymes

11 22 33

44

55

Signal TransductionSignal TransductionChanging a signal from 1 form to anotherChanging a signal from 1 form to another

Signal Transduction PathwaySignal Transduction Pathway – all the steps – all the steps from the signal binding to the end resultfrom the signal binding to the end result

A cascade of activation of enzymesA cascade of activation of enzymes Leads to amplification of the signal Leads to amplification of the signal

because one active enzyme activates a because one active enzyme activates a bunch of others amplification videobunch of others amplification video• May directly activate enzymes that activate May directly activate enzymes that activate

other enzymesother enzymes• May activate second messengers that activate May activate second messengers that activate

enzymesenzymes

Amplification of the SignalAmplification of the Signal

How do you convert an electrical to a How do you convert an electrical to a chemical signal?chemical signal?

Example of Signal Transduction

Two Major Types of Signal Two Major Types of Signal Transduction ReceptorsTransduction Receptors

G-Protein ReceptorsG-Protein Receptors - Lead to activation of - Lead to activation of G proteins – Activate one enzyme – which G proteins – Activate one enzyme – which then sets off the cascade or opens an ion then sets off the cascade or opens an ion channel – may set off multiple reactionschannel – may set off multiple reactions

Tyrosine Kinase ReceptorsTyrosine Kinase Receptors - Lead to - Lead to activation of tyrosine kinases – triggers activation of tyrosine kinases – triggers multiple signal transduction pathways at multiple signal transduction pathways at onceonce- Growth factors work through this path- Growth factors work through this path

G Protein Linked ReceptorsG Protein Linked ReceptorsAn OverviewAn Overview

800 human genes that encode G Protein Linked 800 human genes that encode G Protein Linked Receptors (4% of the human genome)Receptors (4% of the human genome)

50% of all medicines target these receptors50% of all medicines target these receptors They are used for vision (convert light to cellular They are used for vision (convert light to cellular

signals), smell, mood regulators (serotonin and signals), smell, mood regulators (serotonin and dopamine), activate immune cells, control blood dopamine), activate immune cells, control blood pressure, heart rate, and activate tumor growth pressure, heart rate, and activate tumor growth and metastasisand metastasis

They bind to hormones (350 different kinds for They bind to hormones (350 different kinds for hormones), odors, neurotransmitters, hormones), odors, neurotransmitters, pheromones)pheromones)

G-Protein Linked ReceptorsG-Protein Linked ReceptorsHow they workHow they work

When a ligand binds to a receptor – the receptor When a ligand binds to a receptor – the receptor changes shape and attaches to a G-Protein.changes shape and attaches to a G-Protein.

This changes the shape of the G-protein allowing This changes the shape of the G-protein allowing GTP to displace GDP GTP to displace GDP

When GDP is attached its inactive/ when GTP is When GDP is attached its inactive/ when GTP is attached it activeattached it active

A piece of the G protein falls off and the remaining A piece of the G protein falls off and the remaining piece translocates in the membrane until it hits piece translocates in the membrane until it hits another proteinanother protein

The active G protein activates the protein it hitsThe active G protein activates the protein it hits

To inactivate it – the G protein itself clips the To inactivate it – the G protein itself clips the phosphate off of GTP and it becomes GDP which phosphate off of GTP and it becomes GDP which causes the receptor to go back to its inactive form causes the receptor to go back to its inactive form and resets everything. (part of the G protein is a and resets everything. (part of the G protein is a phosphatase)phosphatase)

Video showing opening of Calcium Channels by G-protein receptors

Video showing activation of adenylate cyclase by G protein receptors

Video showing the action of epineprine on Gprotein receptors to cause teh breakdown of glycogen to glucose

video showing general G-protein mechanisms

G protein receptors and IP3

Videos Showing the Actions of G-protein linked receptors

Tyrosine Kinase ReceptorsTyrosine Kinase ReceptorsAn OverviewAn Overview

90 different genes to encode this 90 different genes to encode this type of receptortype of receptor

Mostly receive growth factors, Mostly receive growth factors, cytokines, and hormonescytokines, and hormones

Examples: Insulin receptor, Examples: Insulin receptor, receptors that stimulate the growth receptors that stimulate the growth of blood vesselsof blood vessels

What’s a Kinase?What’s a Kinase?

An enzyme that adds a POAn enzyme that adds a PO44-- to to

another molecule to activate it (it another molecule to activate it (it usually gets the phosphate from usually gets the phosphate from

ATP)ATP)

Tyrosine Kinase ReceptorsTyrosine Kinase ReceptorsHow They WorkHow They Work

The interior portion of the receptor is a tyrosine The interior portion of the receptor is a tyrosine kinase which phosphorylates tyrosine amino acids kinase which phosphorylates tyrosine amino acids on itself using ATPon itself using ATP

The receptor has 2 halves – each with a series of The receptor has 2 halves – each with a series of tyrosinestyrosines

When the ligand binds – 2 halves of the receptor When the ligand binds – 2 halves of the receptor aggregateaggregate

The tyrosines are phosphorylated and activated – The tyrosines are phosphorylated and activated – each side phosphorylates the other sideeach side phosphorylates the other side

Relay molecules bind to the phosphorylated Relay molecules bind to the phosphorylated tyrosines and get activatedtyrosines and get activated

To inactivate it – phosphatases in the cytoplasm To inactivate it – phosphatases in the cytoplasm and stuck in the cell membrane cleave the and stuck in the cell membrane cleave the phosphates off of the tyrosine kinase receptorphosphates off of the tyrosine kinase receptor

Activation by Tyrosine Kinase Activation by Tyrosine Kinase ReceptorsReceptors

Video on Tyrosine Kinase receptor

activation

Long version describing action of

tyrosine kinase receptors

How the Insulin Receptor Works

Second MessengersSecond Messengers Small – non-protein molecules that can activate Small – non-protein molecules that can activate

a large amount of enzymesa large amount of enzymes Ex. cAMP and calcium, IP3, DAGEx. cAMP and calcium, IP3, DAG Best advantage – small so can diffuse much Best advantage – small so can diffuse much

quicker than enzymes which are bigquicker than enzymes which are big G protein and tyrosine kinase receptors both G protein and tyrosine kinase receptors both

can work via 2can work via 2ndnd messengers messengers

For cAMP:For cAMP: when the receptor is activated when the receptor is activated• it activates adenylate cyclase which creates cAMP it activates adenylate cyclase which creates cAMP

from ATPfrom ATP• The cAMP activates a cascade of kinasesThe cAMP activates a cascade of kinases

ATP and cAMPATP and cAMP

Using Ca++ as a 2Using Ca++ as a 2ndnd Messenger Messenger

Ligand activates receptor which Ligand activates receptor which activates enzymes that cause the activates enzymes that cause the formation of IP3 (from phospholipids)formation of IP3 (from phospholipids)

IP3 opens gated channels and lets Ca IP3 opens gated channels and lets Ca out of the SERout of the SER

Ca binds to Calmodulin protein which Ca binds to Calmodulin protein which activates a host of other kinasesactivates a host of other kinases

Calcium as a Calcium as a 22ndnd

messengermessenger

End Result of Kinase ActivationEnd Result of Kinase Activation Activate many molecules of a single Activate many molecules of a single

enzyme type to make a lot of one enzyme type to make a lot of one productproduct

Activate multiple enzymes to make Activate multiple enzymes to make multiple productsmultiple products

Turn on genes to make a specific Turn on genes to make a specific product by protein synthesisproduct by protein synthesis• Kinase activates a transcription factor Kinase activates a transcription factor

(growth factors work this way)(growth factors work this way)

Receptors that Turn on GenesReceptors that Turn on Genes

Growth factors activate transription Growth factors activate transription factors through a cascade of factors through a cascade of phosphorylationphosphorylation

Steroid hormones – bind to a Steroid hormones – bind to a cytosolic receptor that then cytosolic receptor that then translocates into the nucleus and translocates into the nucleus and binds to the DNA turning on genesbinds to the DNA turning on genes

Action of Steroids Hormones on Intracellular Receptors

How does the same signal have How does the same signal have different effects in different cells?different effects in different cells?

What proteins the receptor activates inside the cellWhat proteins the receptor activates inside the cell The receptor may be different (it would have the same The receptor may be different (it would have the same

shaped pocket)shaped pocket)

Action of Adrenaline on Action of Adrenaline on Different CellsDifferent Cells

Skeletal Muscle – breaks down glycogenSkeletal Muscle – breaks down glycogen Smooth muscle of lungs – relaxes itSmooth muscle of lungs – relaxes it Smooth muscle of BV – contracts itSmooth muscle of BV – contracts it Heart – beat fasterHeart – beat faster

Blood Vessels Lungs

Alpha Adrenergic Receptors Beta Adrenergic Receptors

G protein activates phospholipase C G protein activates adenylate cyclase

2nd messenger IP3 2nd messenger cAMP

Ion channel in SER opened, release Calcium

Calcium response blocked

Causes contraction of smooth muscle and an increase in blood pressure

Relax smooth muscle in lung and can breath easier

When using proteins as the relay When using proteins as the relay molecules, how do you make the molecules, how do you make the reactions happen efficiently in the reactions happen efficiently in the

cytoplasm?cytoplasm? Scaffold Proteins: Scaffold Proteins:

Large proteins Large proteins that hold other that hold other

kinases togetherkinases together Proteins don’t Proteins don’t have to diffuse – have to diffuse – they are already they are already

right thereright there

Examples of Drugs that work by Examples of Drugs that work by blocking or activating receptorsblocking or activating receptors

Blood Pressure Medication – blocks the Blood Pressure Medication – blocks the angiotensin II receptor (angiotensin causes angiotensin II receptor (angiotensin causes the muscle around blood vessels to the muscle around blood vessels to contract)contract)

Anti-histamines block the H1 receptor for Anti-histamines block the H1 receptor for histamineshistamines

Morphine binds to the Morphine binds to the

endorphin receptor whichendorphin receptor which

releases endorphins which releases endorphins which

prevent painprevent painNote: all 3 are G protein receptorsNote: all 3 are G protein receptors

What Happens when receptors are What Happens when receptors are exposed to high amounts of ligand or exposed to high amounts of ligand or

exposed to ligand for a prolonged time?exposed to ligand for a prolonged time? The receptors are moved to the The receptors are moved to the

inside of the cell inside of the cell OROR They aren’t linked to the G protein They aren’t linked to the G protein

anymore anymore OROR They are destroyed by lysosomesThey are destroyed by lysosomes

End Result:End Result:

Decreased sensitivity to the ligandDecreased sensitivity to the ligand

Cause of both drug addiction and type Cause of both drug addiction and type II DiabetesII Diabetes