Signalling Flashcards
why is signalling important in medicine
often conditions are caused by an error in signalling - if we understand signalling, we can improve prognosis and treatment
examples of signals
O2
temperature
hormones/ growth factors
glucose levels
pathogens
Homeostasis
e.g. control of blood glucose levels
- too high = insulin released
- too low = glucagon released
diabetes
result of improper signalling
- type 1 is a lack of sufficient insulin production
- type 2 is reduced responsiveness to insulin target cell
two main methods of transduction
enzyme cascades
second messengers
enzyme cascades
often activated in response to growth factor RTK activation
relay proteins Grb/Sos activate Ras -> activated MAP kinase cascade
- multiple different MAPK cascades for different receptors
second messenger definition
a small molecule produced in large amounts inside a cell after receptor activation e.g. cAMP
second messenger example: adrenaline
GCPR -> adenyl cyclase -> cAMP -> PKA activation -> effector proteins phosphorylated
phospholipase C activation
DAg -> IP3 -> Ca2+ -> Ca- -> CaMKs (enzymes)
possible responses
-gene expression
-protein activity (e.g. phosphorylation alters metabolic enzyme activity)
-protein binding
-protein localisation (e.g. transcription factor activated by moving from cytosol to nucleus)
types of signals
physical - pressure, temperature
electrical - nerve cells
bio(chemical) - hormones
growth factors
hormones
types of hormones
1- amino acid derivatives (Adrenaline)
2- steroid hormones (testosterone, cortisol)
3- eicosanoids (prostaglandins)
endocrine - long distance, via blood
paracrine - short distance, by diffusion
juxtracrine - neighbouring cell, via cell-cell contact
autocrine - same cell
intracellular receptors
testosterone
hydrophobic signal molecules can diffuse through plasma membrane into cell or NO
bind directly to intracellular receptor proteins
hormone-receptor complex acts as a transcription factor
complex binds to DNA and alters gene expression
CSRs
water-soluble/ hydrophilic signal molecules must use a CSR protein (adrenaline/ insulin)
hormone ligand binds to CSR and alters its shape, altering function -> cellular response
types of CSRs
ion-channel-linked (glutamate neurotransmitter)
g-protein-linked (adrenaline, serotonin)
enzyme-linked (key subtype = Receptor Tyrosine Kinases (RTK); growth factors)
ion-channel linked
ion flow into cell changes electrical properties of a cell
- e.g. nerve impulse transmission
G-protein-linked
activated G-protein activated enzyme that passes on signal into cell
- large heterotrimeric G-proteins are not the same a small monomeric g-protein like Ras
signal molecule activated G-protein -> activated an enzyme
-> changes in the cell
G-protein-coupled-receptors (GPCR)
enzyme-linked
signal molecule binds to two parts of enzyme -> creates the active site needed for the changes in the cell
- may be dimeric, binding to the two different molecules to create the catalytic activity in the cytoplasmic domain
- may cause conformational change
protein phosphatase = removes a phosphate group form a target protein
protein kinase = an enzyme that uses ATP to phosphorylate a target protein reversibly
process of enzyme linked receptors
ligand binding -> receptor dimerization and activation -> autophosphorylation -> docking sites -> relay proteins recruited, transmit signal further into cell
specificity of signalling
a cell’s response to a given signal depends on the types and levels of receptors, transducers and effectors are expressed in that cell type;
- genes same; expression differs
-this means that same hormone can have different effects in different tissues
in vivo specificity
specific GPCRs use only a specific subset of G-protein types, which couple to only a specific subset of target proteins
pharmacology with signalling
GF/ RTK pathways often overactive in cancer cells
- activation mutation or overexpression, of RTK or other pathway proteins
treatment = inactivation antibodies or small molecule kinase inhibitors
