Cell signalling pathways
3 steps
Amplification
Transduction
Reception
Response
Signal
Endocrine signalling
Paracrine signaling
Autocrine signalling
Signalling by plasma membrane-attached proteins
Cell surface receptors: Ligand binding
Ion- Channel receptors
Tyrosine kinase-linked receptors
G protein coupled receptors
Receptors with intrinsic enzymatic activity
Ligand binding activates GTP binding protein
Inhibits or activates enzyme for specific 2nd messenger
Can modulate an ion channel to cause change in membrane potential e.g. epinephrine
Changes receptor conformation to open specific ion channel
Eg. Acetylcholine
Stimulates formation of a dimeric receptor
Interacts an activates cytosolic protein tyrosine kinases
Erythropoietin
Changes receptor conformation adn activates intrinsic catalytic activity
Insulin
Controlled by ligand binding
Classification of hormones based on solubility and receptor location
Lipophilic
Hydrophilic with cell surface receptors
Intracellular receptors
Cell-surface receptors
Steroid hormones, thyroxine, Vtiamin D
Prostaglandins
Two subclasses
Peptide hormones
Insulin and glucagon
Small charged molecules
Epinephrine and histamine
Binding of signalling molecule to receptor intiiates signalling pathways
Examples
Increased glucose uptake
Expression of growth promoting genes
Energy-store mobilization
Epinephrine and B-Adrenergic receptor
Insulin and insulin receptor
Epidermal Growth Factor and its receptor (EGF)
Second messengers
Binding of ligands to many cell surface receptors leads to increase or decrease in intracellular signalling molecules
Diffuse to other compartments of cell and influence gene expression
Signal amplified in generation of second messengers
Examples
Calcium ion
Inositol 1,4,5-triphosphate
cAMP, cGMP
Diacylglycerol (DAG)
Protein phosphorylation
Specific enzymes called protein kinases phosphorylate target proteins
ATP is most common donor of phosphate groups
Transfer groups from ATP to specific serine, theonine and tyrosine residues on specific proteins.
Protein dephosphorylation
Phosphoates catalyse the hydrolytic removal of phosphate groups
De- and phospho are not reverse of each other. Each is irreversible
Phosphorylation of specific substrate only takes place in presence of specifc protein kinase
De- only takes place in presence of a specific phosphotase
Protein kinases and phosphates work independently but in balance to regulate function of proteins
Free energy is large- can change conformational equlibrium between different functional states of protein.
Used as the phosphoryl group donor links energy status to regulation of metabolism
Phosphate groups adds 2 negative charges to protein
Forms 3 or more hydrogen bonds
Allows new electrostatic interactions
Allows specific interactions with other hydrogen-bond donors
When enzymes activate enzymes
no. of affected molecules Increases in an enzyme cascade
cAMP
Alters quaternary structure of Protein kinase A to activate it
PKA is tetramer
2 regulatory subunits and 2 catalytic subunits R2C2
Without this it is catalytically inactive
GPCR
G-Protein coupled receptors
Delays information from signals
Photons, hormones, neurotransmitters
Contains seven helices that span membrane bilayer
Transmembrane helix (7TM)
Conformation changed by cytoplasmic loops and c-termini in response to ligand binding
Activates G-proteins
Smell
Taste
Neurotransmission
Hormone Action
Hormone secretion
Control of blood pressure
Embryogenesis Development
Vision
Viral infection
3D structure
3D structure of GPCR rhodopsin
Takes part in visual signal transduction
1st GPCR structure to be established
Ligand binding site near extracellular surface
Cyclic AMP activates protein kinase A by altering quaternary structure
Tetramer: 2 regulatory subunits, 2 catlytic subunits
Termination of signal pathway
G proteins hydrolyse GTP to GDP thus resetting themselves. Intrinsic GTPase activity
click to edit
G protein coupled receptors
Relay information from diverse signals eg. photons, hormones, neurotransmitters
7 helices which span membrane bilayer
7Transmembrane helix receptors
Cytoplasmic loops and C termini change conformation in response to ligand binding, activating G proteins
Importance
Involved in diseases
Target of half of pharmaceutical drugs