Lecture 23: Catalytic Receptors Flashcards
Autonomic Transmitters:
N-cholinergic receptors
-N-cholinergic receptors are ion channels
they Signal through membrane potential
Autonomic Transmitters:
b-adrenergic receptors
- b-adrenergic receptors are GPCR
they Signal through second messengers e.g. cAMP
Glucose Regulation
- Skeletal muscle;
Skeletal muscle; adrenaline causes glycogen break down.
What is Islets of Langerhans?
What does it do? blood? loop? pathway?
- Insulin released from b-cells in the islets of Langerhans.
- Increased blood glucose causes insulin release
- Insulin causes blood glucose to fall
- Negative feedback loop
- Islet cells are receptor, afferent pathway and central processor.
- Insulin is the efferent pathway
Release of Insulin STEPS? (9)
- Glucose enters istle cells through *GLUT2 glucose transporter
- Increased blood glucose→ more glucose enters cell
- More glucose→ entry more ATP production
- ATP binds to and CLOSES *KATP channels
- Less K+ efflux depolarizes the cell
- Depolarization open Ca2+ channels
- Calcium binds to SYNAPTOTAGMIN (just like in nerves)
- SNARE proteins change conformation trigger exocytose of vesicles
- Insulin released (just like neurotransmitter release
Insulin Release Glucagon: 3
- Glucagon acting through Gs also stimulates insulin
- Gs activates adenylate cyclase, produces cAMP, turns on PKA that phosphorylates proteins.
- Adrenaline via a2-receptors acting on Gi inhibits insulin release by suppressing PKA
What does Insulin do (Muscle): 8
- Increased glucose uptake into skeletal muscle cells
- Insulin sensitive GLUT4 glucose transporters inserted in cell membrane
- Cells have vesicles with GLUT4 in the vesicle membrane
- Binding of vesicles to the cell membrane adds glucose transporters to the cell membrane
- Turns on synthesis of glycogen (stores glucose)
- Increased production of key glycolytic enzymes
- Turns on protein production in general
- Turns off use of fat as energy, store more fat
How does Insulin Receptor? =4
- Insulin receptor is a RECEPTOR TYROSINE KINASE.
- Tyrosine kinases are a common group of catalytic receptors.
- Receptor tyrosine kinases
- Tyrosine kinase associate receptors
What does a KINASE USE?
A kinase used ATP to phosphorylate something
What does a Phosphatase do?
A phosphatase unphosphorylates something
Protein kinases come in two groups:
- Serine/threonine kinases e.g. myosin light chain kinase
- Tyrosine kinases e.g. Insulin receptor
Receptor tyrosine kinases are?
In Insulin receptor?
- Receptor tyrosine kinases: are them selves enzymes which are turned on by their ligand
- Insulin receptor, platelet derived growth factor, nerve growth factor, many growth factor receptors.
Tyrosine kinase associated receptors have:
eg.
Tyrosine kinase associated receptors have the kinase as a separate subunit that binds the receptor
- Growth hormone and erythropoietin (EPO) receptors
Five known types of catalytic receptor:
- Tyrosine kinases
- Receptor serine/threonine kinase
- Receptor tyrosine phosphotases
4.Receptor guanylate cyclase
Tyrosine kinases = 3
- Receptor tyrosine kinase
- Tyrosine kinase associated receptors
- Most common
Receptor serine/threonine kinase (rare)
- RARE
-Phosphorylate target proteins on serine or threonine
Receptor tyrosine phosphotases (very rare)
- VERY RARE
- Dephosphorylate target protein on a tyrosine
Receptor guanylate cyclase
(guanylyl cyclase, guanyl cyclase)
- (guanylyl cyclase, guanyl cyclase)
- Activated by NO= nitric oxide makes cGMP from GTP
- Similar to adenylate cyclase
Effects of Insulin
How many things can one receptor do?
Lots!
Needs more simplification
SLIDE 16
Cellular Actions of Insulin: 5
- Very very complex, many different pathways and interacting signal pathways get activated.
- No small molecule second messengers but a great many protein kinases
- Much of the signalling is through protein phosphorylation
- Modifies existing proteins
- And modified DNA transcription
Insulin Effect: 2
- Autophosphorylation
- Protein Kinase B
Protein Kinase B Pathway: 5
- Insulin binding causes insulin receptors to autophosphorylate, i.e. they phosphorylate them selves.
- A collection of proteins collectively called INSULIN RESPONSE SUBSTRATES (IRS) are phosphorylated.
- Through intermediate steps that phosphorylates the membrane lipid phosphatidylinositol to PHOSPHATIDYLINOSITOL-3-PHOSPHATE (do not confuse with INOSITOL TRIPHOSPHATE).
- Activates (through more steps) PROTEIN KINASE B (PKB) also called Akt.
- PKB turns on glycogen synthesis and adds **GLUT 4 to the cell membrane
Insulin and Gen Expression (10)
- Ligand binding causes receptor dimerization.
- the activated RTK phosphorylates itself.
- GRB2, an SH2-containing protein, recognises the phosphotyrosine residues.
- the binding GRB2 recruits SOS.
- SOS activates Ras by causing GTP to replace GDP on Ras.
- the activated GTP-Ras recruits Raf-1 and activates it.
- Raf-1 phosphorylates and activates MEK.
- MEK phosphorylates and activates MAPK.
- MAPK works as an important effector molecule by phosphorylating many cellular proteins.
- MAPK translocates to the nucleus where it phosphorylates a transcription factor.
MAPK Pathway: 6
- Insulin binding causes insulin receptors to autophosphorylate, i.e. they phosphorylate them selves.
- Through many intermediate steps mitogen activated protein kinase (MAPK) gets activated.
- MAPK translocated to the cell nucleolus
- Phosphorylates transcription factors and changes gene expression
- General increase in protein synthesis
- Specific increase in key glycolysis pathway enzymes e.g. Hexokinase
Insulin Signalling: 7
- Two major pathways (an over simplification)
- Signals through PI-3P and PKB, activated glycogen synthesis and translocates GLUT 4 glucose transporters to the cell membrane
- Signals though MAPK, change gene expression.
- Changes in gene expression alter the amount of an enzyme in a cell not just the activity of previously present enzymes.
- Many steps means a lot of signal amplification
- But also slow response time
- Changes in gene expression slow to turn on but long lasting
Summary 6
- Entry of glucose into b-cells closes ATP sensitive K+ channels, depolarizes the cells and causes exocytosis of insulin.
- Insulin acts on skeletal muscle to increase glucose uptake, glycogen synthesis and change gene expression
- Insulin receptors are tyrosine kinases
- 5 types of catalytic receptor
- Insulin receptor leads to activation of PKB that causes increased glucose uptake and glycogen synthesis
- Also activates MAPK that changes gene expression