Lecture 11: cell to cell communication

Question 1

Direct signalling uses

Answer 1

Gap junctions, which connect cells directly touching each other

• the signal therefore passes directly from one cell to another without traversing extracellular space (stays in the cytoplasm)
• ie. contraction of cardiac cells

Question 2

Gap Junctions

Answer 2

• specialized protein complexes create an aqueous pore between adjacent cells
• can be opened or closed for regulation
• allows rapid communication over short distances

Question 3

Indirect signals must be:

Answer 3

• synthesized & stored, released, transported
• received and transduced by the receptor
• transduced and amplified by signal transduction pathway, so target cell can generate a response

Question 4

Chemical Messenger-problems

Answer 4

• must be transport in aqueous solution, if messenger is not water soluble it will have trouble over long distances
• message has to penetrate cells, so if it is not lipid soluble it cannot send its signal

Question 5

Receptor locations

Answer 5

1. embedded in the membrane with binding site outside the cell
2. inside the cell

Question 6

Ligand binding

Answer 6

-ligand or chem messenger binds to the receptor to induce change in its conformation and activates the signal transduction pathways that cause response in the cell

Question 7

Receptor Specificity

Answer 7

-ligand binding site has a specific shape, so only some molecule fit its structure

Question 8

agonists and atagonists

Answer 8

• chemicals that bind to and activate receptors are agonists, the mimic natural ligands
• antagonists bind to the receptor but block the action of the natural ligand

Question 9

Adenosine

Answer 9

-a purine nucleoside functions for: energy transfer (atp, adp), signal transduction (cAMP), promotes healing, and as a neurotransmitter inhibits activity in the CNS*** causing sleepiness and preventing arousal after prolonged mental activity

Question 10

Caffeine, adenosine antagonist

Answer 10

• binds to and blocks adenosine receptors in the CNS
• is both water and lipid soluble, can cross blood-brain barrier
• cells respond by increasing amount of adenosine released, which is why coffee drinkers must have more to overcome increasing adenosine levels

Question 11

Receptor Saturation

Answer 11

• single cell expresses many molecules of a given receptor
• the more receptors that are bound to ligand, the larger the magnitude of the response
• saturation=all receptors are bound to ligand
• increasing # of receptors means increased response

Question 12

up and down regulation

Answer 12

of receptors on a target cell can change over time

Question 13

Receptor sensitivty

Answer 13

-affinity of a receptor for a ligand

Question 14

Dissociation constant Kd=

Answer 14

the ligand concentration at which HALF the receptors are bound to ligand

Question 15

Affinity constant

Answer 15

Ka=1/Kd; as Ka increases, response increases

Question 16

Inactivation of ligand signaling

Answer 16

1. remove from ECF

2. terminate receptor activation

Question 17

Removing ligand from ECF

Answer 17

• enzymes in liver and kidney break down hormoes, removing them from the blood (slow)
• ligand will be destoryed at the cellular levels (fast)

Question 18

Terminating receptor activation

Answer 18

-as concentration of a hormone in the ECF decreases, bound molecules of that hormone will dissociate from their receptors

Question 19

inactivation of ligand signaling

Answer 19

-receptor down regulation, receptor sequestration, receptor inactivation, inhibitory proteins, signal protein inactivation

Question 20

Signal transduction pathways amplify signals

Answer 20

-convert conformational change of an activated receptor into an intracell response
-signald transduction pathways have multiple steps
-greater the number of steps, the greater the amp
“each activated receptor activated many substance A, which activates many B, etc)

Question 21

4 types of receptors

Answer 21

1. intracellular
2. ligand-gated ion channel
3. receptor-enzyme
4. G-protein-coupled receptor

Question 22

Intracellular receptor location

Answer 22

in cytoplasm (move to nucleus once bind to ligand) or in the nucleus, bound to DNA

• ex: ER-a estrogen receptor, found in hypothalamus, ovary, uterus, and mammary glands
• over-expressed in 70% of patients with breast cancer

Question 23

intracellular receptors regulate transcription

Answer 23

• of traget genes by binding to specific DNA sequences and increasing or decreasing mRNA production
• have 3 domains: ligand binding, DNA binding, and transactivation
• many endocrine hormones bind to them (estrogen, testosterone, etc)

Question 24

Ligand-gated ion channels

Answer 24

• when activated by binding ligand, the receptor changes shape, opening or closing the ion channel, allowing ions to pass and change MP
• ie. Nicotinic ACh receptor

Question 25

Receptor enzyme

Answer 25

- when activated the catalytic domain starts a *phosphorylation cascade* - 3 subtypes: guanylate cyclase (few), tyrosine kinase (majority in animals), serine/threonine kinase (many)

Question 26

Receptor guanylate cyclase

Answer 26

- when activated catalyzes conversion of GTP to cGMP - cGMP acts as secondary messenger in signal transduction pathway - ie. atrial natriuretic peptides

Question 27

receptor serine threonine kinase

Answer 27

- serine and threonine residues phosphorylated by protein, initiating a long phosphorylation cascade - ie. transforming growth factor beta

Question 28

receptor tyrosine kinases

Answer 28

- phosphorylation of the receptor creates high affinity docking sites for the binding of specific intracellular signaling proteins - intracellular proteins bind between themselves, becoming phosphorylated and activated - often bind growth factors or insulin, and are involved in cell growth and proliferation - ie. Ras, GAPs, GNRP

Question 29

tryosine kinases and growth factor

Answer 29

- activated Ras signals start amplification cascade/phosphorylation cascade - MAP-kinase phosphorylates a variety of target proteins (MAPK=mitogen activated protein kinase - mutation of this receptor and transduction pathway can cause cancer, due to its effect on cell growth and metabolism

Question 30

Vascular endothelial growth factor (VEGF) receptors

Answer 30

- tryosin kinase receptors located in cell membrane of endothelial cells lining blood vessels - when activated by VEGF, induces cell proliferation and growth of new blood vessels (angiogenesis) - VEGF is produced by cells which are not receiving enough oxygen

Question 31

G-protein-coupled receptors (GPCR)

Answer 31

- transmembrane receptors which interact with heterotrimeric G proteins - ligand bindings induces conformational change, causing the alpha subunit to release GDP and bind GTP - alpha and By subunit (aka G protein) become active and dissociate, allowing them to move through membrane to interact with ion channels or amp enzymes and initiate or mute a response - alpha subunit remains active until it hydrolyzes GTP, at which point it becomes inactive and reassembles with By

Question 32

speed of alpha subunit hydrolysis of GTP can be regulated

Answer 32

- alpha subunits are slow GTPase | - RGS are proteins that control speed of a subunits' hydrolysis of GTP, activating RGS speeds up hydrolysis

Question 33

GPCR signal transduction pathways

Answer 33

1. a and By can stimulate ion channels to open or close, changing MP and ion concentration (ie. acetylcholine on cardiac cells) 2. a and By subunits activate or inhibit amplifer enzymes such as adenylate cyclase, guanylate cyclase, phosphodiesterase, phospholipase ie. for cAMP signal trans. path. Gs activates adenylate cyclase and Gs inhibits it - can also regulate levels of cAMP to reg. levels of active PKA

Question 34

GPCR example: taste receptors

Answer 34

- modified epithelial cells that release neurotransmitter onto afferent neurons - each receptor expresses more than one type of taste receptor protein

Question 35

G-proteins regulate activity of phosphodiesterase

Answer 35

dark: -Na+ gate channel maintained open by cGMP that bind on it - Na+ enters the cell, contributes to resting value of Em

Question 36

G-proteins regulate Phospholipase C

Answer 36

- phos. C breaks down PIP2 into DAG and IP3 - DAG activates PKC, which initiates a phosphorylation cascae - IP3 releases Ca2+ from endoplasmic reticulum as a secondary messenger

Question 37

GPCR-Ca2+ activates calmodulin

Answer 37

- some g-proteins open or close Ca2+ channels directly or indirectly - Ca2+ binds to calmodulin & binding 4Ca2+ activates calmodulin - activated calmodulin regulates over 100 cellular proteins ex: increased Ca2+activates calmodulin->activates CaM kinase II->phosphorylase tyrosine hydrolase->increase synth of catecholamines

Question 38

GPCR example: angiotensin receptor

Answer 38

- hormone produced by liver that increases blood pressure - found in smooth muscles lining blood vessles and activates the subunit of G-proteins, activation phospholipase C - IP3 releases Ca2+ from the ER, stimulating muscle contraction=vasoconstriction

Question 39

Signal transduction pathways can interact with each other:

Answer 39

- when bound to Ca2+, calmodulin interacts with adenylate cyclase, which produces cAMP - Ca2+-calmodulin can also interact with cAMP phosphodiesterase, which breaks down cAMP - cAMP activates PKAA, which can phosphorylate Ca2+ channels and pumps, increasing or decreasing their activity