Hormones

4 types of receptors

* Steroid receptors
* G-protein coupled receptors
* Ligand gated ion channels
* Enzyme linked receptors

Endocrine signalling and examples

Hormones secreted into blood by endocrine gland

* Cortisol
* Insulin
* Adrenaline
* Glucagon

Paracrine signalling and examples

Non-hormonal signals released by individual cells (not glands)

* Growth factors
* Cytokines
* Immune signals

What can send direct contact

Adhesions (or lack of) can send a signal

Name 4 types of signals

* Endocrine signalling
* Paracrine signalling
* Direct contact
* Synaptic signalling

How do steroid receptors work

1. Steroid binds to steroid receptor
2. Dimerisation occurs and receptors come together
3. Receptors relocalised to the nucleus
4. Bind to specific DNA sequences and influence activation of initiation complexes
5. Initiation complexes bind to promoter to stimulate RNA polymerase II for gene transcription

What are the 2 mechanisms by which membrane receptors can trigger responses

Second messengers

Kinase activation

How do receptors work

1. Receptor and ligand bind
2. Conformational change occurs of inside of receptor
3. Triggers cell signalling machinery to evoke cellular response

How do kinases work?

Add phosphates to specific targets to change the target activity

What senses blood glucose

islet cells

name of hormone which responds to low glucose

glucagon

What is normal blood glucose

5

What is considered hypoglycaemia

2

What is considered hyperglycaemia

10

What properties of glucose mean it causes issues if too high

* chemically active
* osmotically active

Effects of glucorticoids on blood glucose

* When low blood glucose, produced by adrenal gland
* Triggers transcription of a set of genes
* Upregulates genes which code for enzymes for glucose production

Effects mediated by increased enzyme synthesis on

* Liver
* Muscle
* Adipocytes

Liver - increased gluconeogenesis

Muscle - increased protein catabolism

Adipocytes - increased lipolysis

Effect of hormone sensitive lipase

* Breakdown of fat to produce fat and fatty acids in adipocytes

What is hormone sensitive lipase produced in response to

Adipocytes respond to cortisol by producing more of hormone sensitive lipase

Function of PEP carboxy kinase

gluconeogenesis

Glucose-6-phosphatase function

Pass glucose into blood

Effect of high glucose on islet cells

* \
* Islet cells have lots of fuel
* Undergo glycolysis
* AMP/ATP decreases
* Insulin produced
* Increased insulin prevents glucagon

Effect of low glucose on islet cells

* Islet cells have less fuel for glycolysis
* Due to increased AMP/ATP
* Detected by B cells
* Insulin not released
* No feedback on glucagon a cells
* Glucagon released

Effects of glucagon

Indicates the fasting state
Stimulates catabolism

* Glycogen breakdown
* Fat breakdown
* Gluconeogenesis

Target tissues of glucagon

Liver

Adipocytes

Subunits of GPCRs

__3 subunits__

G-alpha subunit (different ones exist to exhibit a diff response)

BY (2 subunits)

Mechanism of GPCRs

1. Receptor and ligand bind
2. Conformational change
3. Receptor binds to G-alpha subunit
4. Binding triggers


1. GDP release
2. GTP uptake
3. Forms GaS bound to GTP – binary switch
4. When GTP bound → turned on, can interact with cellular proteins. When GDP bound → cant interact with other proteins so no signal
5. Adenylate cyclase binds to GTP-bound GaS causes lots of ATP → cAMP so cAMP floods the cell to act as a 2nd messenger and stimulate many targets

When G-protein receptor bound to GTP

turned on, can interact with cellular proteins

What turns on PKA

cAMP

Function of PKA

leads to activation of glycogen phosphorylase

glycogen phosphorylase breaks down to glycogen to liberate glucose-1-phosphate

Effect of adrenaline on cardiac muscles

Phosphorylates calcium channels

More calcium influx so greater muscle contraction of heart in response to adrenaline

How are signals turned off (G proteins)

G proteins can hydrolyse GTP → GDP

* Inactive as GDP = Turned off

Removal of cAMP

* Phosphodiesterase cleaves cAMP into AMP which terminates the signal
* PDE 3 inhibitors can be used to treat heart failure by boosting cAMP levels to keep PKA levels high

How is insulin synthesised?

1. **RER**
Translation of messenger insulin occurs on the side of RER and protein produced fed into the lumen
Once produced, signal sequence fed off
2. **Golgi**
Proinsulin
C-peptide cleaved off
Can be used as a measure of insulin as proportional to amount of insulin produced
3. **Secretory vesicle (bud from golgi)**
Fuse with plasma membranes to secrete insulin

What type of cells secrete insulin?

beta-cell

why is insulin release describe as biphasic?

1. Release of preformed insulin when secretory vesicles fuse (rapid)
2. Synthesis and release of new insulin (slower)

What does insulin cause?

1. Activates pyruvate kinase
2. Activates pyruvate dehydrogenase
3. Stimulates activity of acetyl-coA-carboxylase
a. Fatty acid production, fat storage
4. Insulin signalling leads to dephosphorylation of HSL by activation of phosphatase, so fat no longer broken down

Effects of glucagon vs insulin on hormone sensitive lipase

* Glucagon signalling leads to phosphorylation of HSL, stimulation of breakdown of fats
* Insulin signalling leads to dephosphorylation of HSL by activation of phosphatase, so fat no longer broken down

Insulin stimulates

* Glucose uptake – regulated by glucokinase
* Fatty acid synthesis
* Glycogen synthesis
* Glycolysis and pyruvate oxidation (entry in TCA)

Insulin inhibits

* Gluconeogenesis
* Fatty acid oxidation
* Lipolysis

Type of receptor for insulin

enzyme linked receptor

Insulin binds to a muscle cell, what happens next?

1. Kinase activity activated


2. Receptor tail covered in phosphorylated tyrosine residues
3. Pl3-kinase binds to receptor tail
4. Binding activates Pl3-kinase and Pl3-kinase phosphorylates 3rd space of PIP2 producing PIP3
5. AKT recognises the production of PIP3 and binds to it
6. Signal generated which results in the translocation of the GLUT 4 vesicles
7. GLUT 4 vesicles fuse and glucose can enter the cell

Insuline binds to a liver cell, what happens?

1. Insulin binds to receptor
2. Kinase activity activated
3. Receptor tail covered in phosphorylated tyrosine residues
4. Pl3-kinase binds to receptor tail
5. Binding activates Pl3-kinase and Pl3-kinase phosphorylates 3rd space of PIP2 producing PIP3
6. AKT recognises the production of PIP3 and binds to it
7. Signal generated which results in effects on translation of genes

Diagnosis of diabetes

* Oral glucose tolerance test
* Urine analysis
* Measuring plasma insulin suggests type 1 or 2 (type 1 will have none present)

Examples of oral manifestations of diabetes

Microangiopathy – causes impaired blood flow to the gums

Increased glucose in saliva – causes oral thrush and bacterial proliferation

Dry mouth (due to dehydration) – promotes caries formation