Lecture 11 Cell communication Flashcards
Adrenaline secreted form, binds to, for the
Adrenal glands, adrenergic receptors, fight or flight
How is adrenaline transported
Blood
every cell exposed yet only some have correct receptors
Describe endocrine signalling
- Long distance: a cell signals to cells distributed widely in body
- A Hormone is a chemical mediator that is released in one part of the body but regulates the activity of cells in other parts of the body
What drug is specific for beta 1 adrenergic receptors
Bisoprolol
This is only expressed in the heart so the it is less responsive to adrenaline, yet the rest of the body is unaffected.
Result of hormones being present in low concentrations
Receptor specific and sensitive to change
Synaptic signalling
Physical linkage
Target determined by neurones that synapse onto them
Gateway between neuronal and endocrinological systems
Hypothalamus/pituitary gland
What makes up cholesterol
Lipid - hydrophobic
Alcohol - hydrophilic
Structure of cholesterol allows it to
travel through PM and dissolve in aq solution
% of PM made up by cholesterol
30
How much cholesterol is synthesised per day
10g in 37 step biosynthetic pathway
Cholesterol is the precursor for
Steroid hormone
4 examples of steroid hormones
Vit D3
Testosterone
Cortisol
Estradiol
Steroid hormone structure allows it to
pass through BBB and CM as alcohol/lipid
Structure of nuclear receptors
A/B C terminus C DNA BD D Hinge E Ligand BD F C terminus
DNA binding domain encodes
ZInc fingers that contain 4 cysteine residues that coordinate with a zinc atom to formed a looped structure allowing it to access a major groove of DNA double helix
All nuclear receptors share
The same primary structure
C term - DNA BD - N term
2 forms of nuclear receptors
Inactive - inhibitory proteins present
Active - ligand binds, coactivator proteins, C terminus locks ligand in, high affinity –> conf change –> DNA BD –> transcription
Name 2 transcriptional responses of nuclear receptors
- primary response
2. secondary response
Primary response of steroid hormones
Proteins made by R itself
R-steroid hormone activates primary response genes to form primary response hormones
Secondary response of steroid hormones
DELAYED response
Primary response proteins shut off primary response genes + turn on 2nd response genes to form 2nd response proteins
Example of nuclear receptor
Glucocorticoid receptor
Glucocorticoid receptor detects
Dexamethasone - cortisol
Glucocorticoid receptor location
IC receptor as dexamethasone diffuses through PM
Dexamethasone complex translocates to..
Nucleus
Dexamethasone complex mostly expresses
TF
Consistent with primary/secondary responses
Dexamethasone pathway
GR + HSP70 + FKBP52
+
Dex
–> GR + Dex + DNA + tran machinery
Glucocorticoid receptor mainly target
Metabolism
Catabolism
Biosynthetic pathways
When is Dex/cortisol released
stress
decreased blood glucose
4 main points about glucorticoids
- for medical therapy
- immunosuppression/antiinflamm
- broad effects, different organ systems
- debilitating side effects = bone loss/glucose dysregulation
Describe hypothalamus- pituitary-adrenal axis
- The hypothalamus produce a 41 aa peptide called corticotropin-releasing hormone (CRH).
- This travels to the pituitary gland that releases ACTH which is a peptide hormone. 3. This stimulates the adrenal glands which then release cortisol/dexamethasone
What does cortisol effect
- metabolism
- immune system
- Memory
- electroyltes
Disease of too little cortisol + symptoms
Addison’s disease
• Depression, flu-like symptoms, nausea, weight loss
Types of disease from too little cortisol
- Primary adrenal insufficiency – damage to the adrenal glands so cortisol is not made
- Secondary adrenal insufficiency – lack of ACTH due to lack of activity or damage to pituitary gland so adrenal glands can’t be stimulated
Disease of too much cortisol + symptoms
Cushing’s syndrome
Puffy face, weight gain, increase BP, facial growth
Causes of too much cortisol
Benign adenoma pituitary increases ATCH
LT steroid abuse and use
Insulin controls
Blood glucose levels
Insulin released from
Beta cells, Islets of Langerhans - stimulated after meal
Type 1 diabetes
Destruction of β cells – often as a result of auto-immune attack. This results in high levels of plasma glucose
Prevalence type 1 diabetes
1:300, age 18
Insulin receptor structure
Heterotetramer linked by disulfide bonds
Tyrosine kinase activity
Conformation changes when ligand binds to IR
2 kinases domains closer
Kinase domains trans-phosphorylate
Docking domain, insulin substrate 1 becomes tyrosine phosphorylated
3 major biochemical steps in insulin signalling
- tyrosine phos of R and its substrate IRS
- activation lipid kinase P13K
- activation multiple serine/threonine kinases = AKT
6 step pathway of insulin signalling - more detail
- Insulin binds to IR
- IR tyrosine activated
- Tyrosine phos of IR and IR substrate (IRS)
- P-tyrosine sites on IRS allows binding of lipid kinase P13K which synthesises PIP3 at PM
- PIP3 recrutis PDK and directly phos AKT
and other serine/threonine kinases - AKT phos ser/thr residues substrates
What are the effectors of AKT
FOXO –> glucose production
TSC2 –> mTORC1 –> S6K –> protein synth + –> SREBP1c –> lipid synth
GSK3beta –> glycogen sytnh
TBC1D4 –> glucose uptake
Types of insulin
long acting background insulin replacement
Fast acting bolus for meals
Excess insulin disease and symptoms
Hypoglycaemia - too little blood sugar, brain only metabolisrs glucose, live muscles take up glucose –> unconscious/death
Type 2 diabetes
dysreg lipid,carb,protein metab
impaired insulin sercretion/resistance
Prevalence type 2
1: 17
3. 8m UK
Correlation type 2 diabetes
There is a strong correlation between body mass index and risk of type 2 diabetes
Type 2 diabetes symptoms
Thirsty excess glucose in urine as kidneys cant reabsorb all increased urination weight/muscle loss slow heal cuts/ulcers thrush blurred vision
REmission trial
High intensity weight loss
46% remission 12m, 36% 24m
Summary Remission results
Increase QOL, decrease systolic BP/triglycerides/SAEs 12-24m
Medication type 2
Metformin - antihyperglycameic agent of the biguanide class
Mechanism metformin
Insulin sensitiser - decrease insulin resistance - reduces plasma fasting insulin levels - weight loss
Where and why does metformin accumulate
Positively charged - in cells and mitochondria
Metformin inhibits
Mitochondria complex 1 preventing production of mito ATP –> increased cytoplasmic ADP:ATP and AMP:ATP ratio –> activated AMP-activated protein kinase which regulates glucose metabolism
2 classes of steroid hormones
corticosteroids - cortex adrenal gland
sex steroids - placenta/gonads
corticosteroids e.g. x2
gluco/mineralcorticoids
sex steroids
oestrogen, testosterone, progesterones
