Unit 5 - Cell Communication

Direct communication

diffusion of chemicals through plasmodesmata or gap junctions and direct contact in cell to cell recognition

• ex: immune cells

• fastest

Synaptic

nerves produce neurotransmitters that bind to receptors on an adjacent cell

• milliseconds

Paracrine

local – cell secretes a signal that binds to neighboring cell receptors

• Ex: growth factors, attraction of immune cells

• faster than hormonal slower than synaptic

Hormonal

chemical released into blood and binds to receptors on distant cells

• 10-30 seconds

Receptor Binding Outcomes

Signal binds to the receptor and changes its shape

• cause receptors to aggregate and lead to endocytosis

• open gated channels

• turn on genes (growth factors and steroid hormones)

• activate an enzyme

• lead to cell division or cell death

• Stimulate cell secretion

• Changing cell shape

• Set off muscle contraction

Signal Transduction Pathway

all the steps from the signal binding to the end result

• transducing a signal is changing it form one form to another

• A cascade of activation of enzymes

• Leads to amplification of the signal because one active enzyme activates a bunch of others   

  • May directly activate enzymes that activate other enzymes

  • May activate second messengers that activate enzymes

Signal Transduction in Nerves

1. The neurotransmitter binds to a receptor on the dendrite of a neuron

2. A gated channel opens letting Na+ in - which rushes down the axon

3. This electrical wave caused by the movement of Na+ opens a voltage gated channel in the end of the axon letting Ca++ in from outside the cell

4. Ca++ causes the axon to exocytose the neurotransmitter into the synaptic cleft

5. Therefore a chemical signal was transduced into an electrical signal which was turned back into a chemical signal

6. The released neurotransmitter binds to the receptor on the next cell (another nerve, a muscle, a gland) and the process starts over

G-Protein Receptors

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

Tyrosine Kinase Receptors

Lead to activation of tyrosine kinases which are part of the receptor – triggers multiple signal transduction pathways at once

• Growth factors work through this path

G-Protein Linked Receptors

How they work

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

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

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

• A piece of the G protein falls off (sometimes) and the remaining piece translocates in the membrane until it hits another protein

• The active G protein activates the protein it hits

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

What’s a Kinase?

An enzyme that adds a PO4- to another molecule to activate it

(it usually gets the phosphate from ATP)

Tyrosine Kinase Receptors

How They Work

• The receptor has 2 halves – each with a series of tyrosines on the inside of the cell

• When the ligand binds – 2 halves of the receptor aggregate

• The interior portion of the receptor is a tyrosine kinase which phosphorylates tyrosine amino acids on the other half of the receptor using ATP

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

• Relay molecules bind to the phosphorylated tyrosines and get activated

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

Integrin Receptors

• receptors that connect with ECM and attachment proteins

• regulate the shape of the cytoskeleton

• regulates the cell cycle

• regulates the movement of new receptors into the membrane

Second Messengers

• Small – non-protein molecules that can activate a large amount of enzymes

• Ex. cAMP and calcium, IP3, DAG

• Best advantage – small so can diffuse much quicker than enzymes which are big

• G protein and tyrosine kinase receptors both can work via 2^nd messengers

• For cAMP: when the receptor is activated

  • it activates adenylate cyclase which creates cAMP from ATP

  • The cAMP activates a cascade of kinases

Using Ca++ as a 2^nd Messenger

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

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

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

End Result of Kinase Activation

• Activate many molecules of a single enzyme type to make a lot of one product

• Activate multiple kinds of enzymes to make multiple products (each kinase only activates one type of enzyme)

• Turn on genes to make a specific product by protein synthesis

  • Kinase activates a transcription factor (growth factors work this way)

Stopping any reaction

1.  Ligand must be gotten rid of

   1. Since they all H bond, they will pop out of the receptor

   2. They need to be carried away in the blood, broken down by enzymes, or sucked back up into the axon

2. Everything phosphorylated has to get dephosphorylated

   1. The G protein’s GTP

   2. The TK’s interior

   3. All of the kinases

3. If ions are involved they must be pumped back to where they started

4. If non-ion 2nd messengers are involved, they need to be broken down

5. Basically everything must be undone in the entire signal transduction cascade

6. Phosphatases take the PO4- off

Receptors that Turn on Genes

• Growth factors - activate transcription factors through a cascade of phosphorylation

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

There can be different effects in different cells and different effects in the same cell at different times

• testosterone during fetal dev causes the formation of the male sex organs / at puberty it causes the secondary sex char to form

• a T cell binds to a marker protein during fetal dev - it causes the T cell to kill itself / afterward it causes the T cell to kill the cell with the marker protein it attached to

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

• What proteins the receptor activates inside the cell

• The receptor may be different (it would have the same shaped pocket)

• The presence of 1 signal can affect the response of another

Action of Adrenaline on Different Cells

• Skeletal Muscle – breaks down glycogen

• Smooth muscle of lungs – relaxes it

• Smooth muscle of BV – contracts it

• Heart – beat faster

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

• Scaffold Proteins: Large proteins that hold other kinases together

• Proteins don’t have to diffuse – they are already right there

Examples of Drugs that work by blocking or activating receptors

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

• Antihistamines block the H1 receptor for histamines

• Morphine binds to the endorphin receptor which releases endorphins which prevent pain

Note: all 3 are G protein receptors

What Happens when G protein receptors are exposed to high amounts of ligand or exposed to ligand for a prolonged time?

• They aren’t linked to the G protein anymore (internal phos prevents their interaction with G protein) THEN

• The receptors are moved to the inside of the cell by endocytosis THEN

• They are destroyed by lysosomes THEN

• mRNA levels reduce so new receptor production is decreased

End Result: Decreased sensitivity to the ligand - cause of both drug addiction and type II Diabetes

Homeostasis and cell comm.

What happens if you get too hot or too cold?

• homeostasis - keeping the same the same (not everything is maintained in homeostasis) (only to keep stuff that you’ll die if you don’t have in the right amount the same)

• homeostasis works like a thermostat in you house. Sensors in the thermostat (receptors), when house temp starts to drop thermostat sensors send electrical signal to furnace until it’s back up, then sensors turn it off

• when your temp isn’t normal body temp (ex: it rises). hypothalamus sense temp has gone up. blood vessels dilate to let more blood flow to surface of the skin to radiate out more heat. also signal sweat glands to let out hot liquid from the blood. once normal, shut that system off.

• when it’s lower your blood vessels contract and sweat glands remain inactive. shiver so you can do muscle contraction and cellular respiration to produce more heat. if that still doesn't work, cut off circulation to fingers and toes to keep the core of the body (brain and heart) to stay alive.

• negative feedback - when it’s shut off for homeostasis

What happens if you go to Denver?

• higher up so less oxygen (normally breathe in 20% oxygen, Denver is much less)

• If you have reduced levels of oxygen, the receptors that measure that are in the kidney. If they detect it they produce a hormone called enthropoitein, which binds to the cells with the receptors for that (located in the bone marrow), telling the cells to divide to carry more oxygen. Increased blood cells only last around 2 weeks.

• blood doping - taking out your blood cells and then putting them back in to increase athletic abilities (test for this in the olympics)

What if you eat unhealthy and don’t get enough calcium?

• If you don’t have enough calcium in your blood, you die

  • muscle contraction and nerve conduction rely on it

  • it’s very tightly regulated in your blood

  • CANNOT LET IT GET LOW

    • happens if you don’t eat healthy

  • need vitamin D to absorb it (calcium)

• macrophages in the bone that release enzymes to break down the ECM

• osteoporosis - when your bones are getting weak

• when something goes wrong with homeostasis it’s a disease

• calcitonin acts as an inhibitor taking excess calcium out of your blood

Viruses use receptors

• have a lot of proteins on the outside

• If one of the proteins matches the shape of the receptors, it can bind to it and endocytosis into the cell where it’ll make millions of copies of itself

• How does HIV get in?

  • look at image in slideshow

  • binds to the receptor in T cells

  • gets endocytosed into the cell

  • Reverse transcriptase takes rna copy and makes DNA

    • the DNA has an enzyme to insert it in the genome