Lecture 13. Signalling Through G-Protein Coupled Receptors Flashcards
When does the B-Adrenergic receptor signalling pathway become activated ?
When the body is under stress
What can a single hormone receptor complex stimulate ?
Nucleotide exchange in many G-protein heterotrimers
What is step 1. in the B-Adrenergic signalling pathway ?
Epinephrine binds to the receptor resulting in an activated receptor
What is step 2. in the B-Adrenergic signalling pathway ?
GTP is exchanged for GDP resulting in amplification and an activated G protein
What is step 3. in the B-Adrenergic signalling pathway ?
There is a protein-protein interaction resulting in amplification and an activated adenylate cyclase
What is step 4. in the B-Adrenergic signalling pathway ?
An enzymatic reaction occurs resulting in amplification and increased cyclic AMP
What is step 5. in B-Adrenergic signalling pathway ?
The increased cyclic AMP activates protein kinase A and other effector enzymes
What is step 6. in B-Adrenergic signalling pathway ?
Each protein kinase A phosphorylates hundreds of proteins
How is the B-Adrenergic signalling pathway terminated ?
G-proteins spontaneously hydrolyse GTP to GDP thus resetting themselves
What ability do G-proteins have ?
Intrinsic GTPase activity
How is the signal transduction by the G-protein coupled receptor terminated in B-Adrenergic pathway ?
- Dissociation of signalling molecules from receptor
2. Phosphorylation of cytoplasmic C-terminus of receptors and subsequent binding of B-arrestin
What is the function of B-arrestin?
Desensitisation
Under stress all tissues have an increased need for ??
Fuels like glucose (glycogenolysis) and fatty acids (lipolysis)
Where do liberated glucose and fatty acids as a result of epinephrine/adrenaline bind to ?
Hepatic and adipose cells respectively
Where else can epinephrine bind to ?
B-Adrenergenic receptors on heart
What do B-Adrenergic receptors on the heart do ?
Increase the heart contraction rate which increases blood supply to the heart
In the adipose tissue, which hormone induces a rise in cyclic AMP ?
- Epinephrine
- ACTH
- Glucagon
In the liver, which hormone induces a rise in cyclic AMP ?
- Epinephrine
- Norepinephrine
- Glucagon
In the ovarian follicle, which hormone induces a rise in cyclic AMP ?
- FSH
2. LH
In the adrenal cortex, which hormone induces a rise in cyclic AMP ?
ACTH
In the cardiac muscle, which hormone induces a rise in cyclic AMP ?
Epinephrine
In the thyroid gland, which hormone induces a rise in cyclic AMP ?
TSH
In the bone, which hormone induces a rise in cyclic AMP ?
Parathyroid Hormone
In the skeletal muscle, which hormone induces a rise in cyclic AMP ?
Epinephrine
In the intestine, which hormone induces a rise in cyclic AMP ?
Epinephrine
In the kidney, which hormone induces a rise in cyclic AMP ?
Vasopressin
In the blood platelets, which hormone induces a rise in cyclic AMP ?
Prostaglandin I
What is the cellular response to a rise in cyclic AMP in adipose tissue ?
- Increase in hydrolysis of triglycerides
2. Decrease in amino acid uptake
What is the cellular response to a rise in cyclic AMP in the liver ?
- Increase in conversion of glycogen to glucose
- Inhibition of glycogen synthesis
- Increase in amino acid uptake
- Increase in glucogenesis
What is the cellular response to a rise in cyclic AMP in the ovarian follicle ?
Increase in synthesis of estrogen and prostesterone
What is the cellular response to a rise in cyclic AMP in adrenal cortex ?
Increase in the synthesis of aldosterone and cortisol
What is the cellular response to a rise in cyclic AMP in the cardiac muscle ?
Increase in contraction rate
What is the cellular response to a rise in cyclic AMP in the thyroid gland ?
Secretion of thyroxine
What is the cellular response to a rise in cyclic AMP in bone ?
Increase in resorption of calcium from bone
What is the cellular response to a rise in cyclic AMP in skeletal muscle ?
Conversion of glycogen to glucose
What is the cellular response to a rise in cyclic AMP in intestine ?
Fluid secretion
What is the cellular response to a rise in cyclic AMP in kidney ?
Resorption of water ?
What is the cellular response to a rise in cyclic AMP in blood platelets ?
Inhibition of aggregation and secretion
What are three reasons why so many types of signals can be mediated by a single second messenger (cAMP) ?
- Some hormones act by inhibiting adenylate cyclase, lowering cyclic AMP and suppressing phosphorylation by protein kinase A.
- Prostaglandin E1 stimulated cyclic AMP synthesis because its receptors are coupled to stimulatory Gs
- An extracellular signal can have very different effects on different tissues or cell types
What are three factors that effect the extracellular signal on different tissues or cell types ?
- Type of receptor in tissue
- Type of G protein
- The set of protein kinase A target proteins in the cell
What is the fourth factor which effects why so many types of signals can be mediated by a single second messenger (cAMP)?
The confinement of the signalling process to specific regions within the cell
What helps confine a signalling process to specific regions within the cell ?
Adaptor proteins- non catalytic
What do adaptor-non catalytic proteins do ?
Hold together signalling proteins in a complex
What is an example of a adaptor-non catalytic proteins ?
A kinase anchoring proteins (AKAPs)
What are AKAPs ?
Multivalent adaptor proteins
How do AKAPs work ?
One part binds to R subunits of protein kinase A and another to the specific structure within the cell that confines protein kinase A to the vicinity of tjat structure
How does a cell achieve integration of signals ?
By summing the influences that lead to an increase or decrease in cyclic AMP
What do many G-protein coupled receptors do ?
Activate the phosphoinositide cascade
What do second messengers do ?
Relay information from receptor-ligand complex
What does the binding of ligands to many cell surface receptors do ?
Increase or decrease in intracellular signaling molecules
What does the enzyme phospholipase C do ?
Cleaves PIP2 yielding IP3 and DAG
What does IP3 do ?
Increase in cytosolic CA+2
What does DAG do ?
Activate protein kinase C
What does angiotensin II receptor do ?
Binds peptide hormone involved in controlling blood pressure
What is step 1 in the phosphoinositide cascade ?
Ligand binds to g-protein coupled receptor activating the g protein which leads to activation of phospholipase C
What is step 2 in the phosphoinositide cascade ?
Phospholipase C cleaves PIP2 yielding IP3 and DAG
What is step 3 in the phosphoinositide cascade ?
IP3 diffuses through the cytosol and interacts with and opens CA+2 channels in the endoplasmic reticulum membrane
What is step 4 in the phosphoinositide cascade ?
Causing the release of stored Ca+2 ions into the cytosol
What is step 5 in the phosphoinositide cascade ?
Rise in cytosolic Ca+2 facilitates recruitment of protein kinase C to membrane
What is step 6 in the phosphoinositide cascade ?
Protein kinase C becomes activated by membrane bound DAG
What is step 7 in the phosphoinositide cascade ?
Protein kinase C phosphorylates various cellular enzymes and receptors thus altering their activity
What is step 8 in the phosphoinositide cascade ?
As the endoplasmic reticulum Ca+2 stores are depleted, Ca+2 channels in plasma membrane open allowing an influx of extracellular Ca+2
How is the IP3 initiated signals turned off ?
IP3 is rapidly metabolised to inositol which cannot open the calcium channel
How are DAG initiated signals turned off ?
DAG may be phosphorylated to phosphatidate or hydrolysed to glycerol and fatty acids
How does calcium work as a second messenger ?
Calcium binds tightly to proteins and induces conformational changes.
Calcium ions bind tightly to negatively charged oxygen atoms (6-8) which enables it to cross link different segment of proteins inducing conformational changes
What does calcium ion often regulate ?
The regulatory protein calmodulin
What does calmodulin act as ?
A calcium sensor in nearly all eukaryotic cells
How does calmodulin work ?
- When cytosolic Ca+2 level is raised above 500nM, calmodulin is activated by Ca+2 binding.
- It then undergoes a conformational change which exposes hydrophobic surfaces which bind to other places.
What family is calmodulin a member of ?
The EF hand protein
What is the EF hand formed by ?
Helix-loop-helix unit
What else can calmodulin activate ?
Various target proteins such as calmodulin dependent protein kinase
What does calmodulin target in calmodulin dependent protein kinase I >
An alpha helix
What happens after calcium binding in calmodulin dependent protein kinase I ?
The two sets of EF hands of calmodulin clamp down around the target helix
In the pancreas, what hormone induces a rise in calcium ?
Acetylcholine
In the parotid salivary gland, what hormone induces a rise in calcium ?
Acetycholine
In the vascular or smooth stomach tissue, what hormone induces a rise in calcium ?
Acetylcholine
In the liver, what hormone induces a rise in calcium ?
Vasopressin
In blood platelets, what hormone induces a rise in calcium ?
Thrombin
In mast cells, what hormone induces a rise in calcium ?
Antigen
In fibroblasts, what hormone induces a rise in calcium ?
Peptide growth factors
What is the cellular response to hormone induced rise in calcium in pancreas ?
Secretion of digestive enzymes such as amylase and trypsinogen
What is the cellular response to hormone induced rise in calcium in parotid salivary gland ?
Secretion of amylase
What is the cellular response to hormone induced rise in calcium in vascular or stomach smooth muscle ?
Contraction
What is the cellular response to hormone induced rise in calcium in the liver ?
Conversion of glycogen to glucose
What is the cellular response to hormone induced rise in calcium in blood platelets ?
Aggregation, shape change, secretion of hormones
What is the cellular response to hormone induced rise in calcium in mast cells ?
Histamine secretion
What is the cellular response to hormone induced rise in calcium in fibroblasts ?
DNA synthesis, cell division
