Cell Communication
general concepts
o endocrine / paracrine / neural
o receptor protein, target cell, signal transduction
o fast vs slow responses
o intracellular vs cell-surface receptors
intracellular receptors
o mechanism of action, nuclear receptor family of transcription factors
cell-surface receptors
o second messengers
o molecular switches
phosphorylation, kinases / phosphatases, phosphorylation cascades
GTP-binding proteins (G-proteins)
o 3 classes of cell-surface receptors:
1) ion channel-linked
2) G-protein coupled receptors (GPCRs), a, b, g subunits
3) enzyme-linked receptors
o a closer look at GPCRs and enzyme-linked receptors:
GPCRs - downstream targets of activated G-proteins
1) ion channels e.g. Ach-R in cardiac muscle, K channels
2) activate enzymes associated with cytosolic face of membrane
2a) adenylyl cyclase cAMP PKA
2b) phospholipase C IP3+ DAG Ca PKC
2+
Ca as an intracellular signal; calmodulin, CaM-kinases
enzyme-linked receptors
receptor tyrosine kinases (RTKs) and Ra
o RTK, Ras and cancer
Why Cells Communicate
single celled organisms
o ‘social life’ – yeast mating
multicellular organisms, coordination of
o development (from single cell to trillions of cells)
o growth
o coordinating ‘whole body’ growth and development with environment
o day to day physiology
Long vs. Short Range Communication
Endocrine
o if you have the receptor, you can hear the signal (hormone carried in blood stream)
Paracrine
o if you have the receptor and are in close distance, you can hear the signal (local mediator)
Neuronal
o Long distances (down axon to neurotransmitter, across synapse)
Contact-Dependant
o Cells touch (membrane bound signal molecule) Signalling Pathways
Pathway
o signalling molecule synthesized and released by signalling cell
o signal molecule travels to target cell
o signal binds to receptor protein on / in target cell
o signal transduction
o change in target cell behaviour
cell shape, movement
metabolism, secretion
gene expression
Same signal can cause different responses, depending on the target cell.
o acetyl choline (signal)
Heart muscle cell
decreased rate and force of contraction
Salivary gland cell
Secretion
Skeletal muscle cell
contraction
Fast/Slow Responses
o Slow (minutes to hours)
When signal binds to receptor, it can affect nucleus, which will result in RNA being transcribed
which will alter protein synthesis, causing altered cytoplasmic machinery and eventually altered
cell behaviour
o Fast (seconds to minutes)
When signal binds to cell-surface receptor protein, it can follow the intracellular signalling
pathway, cause altered protein function, altered cytoplasmic machinery and eventually altered
cell behaviour
Receptors
Cell Surface Receptor (on plasma membrane)
o Signal molecule is hydrophilic
Bind to receptor protein on plasma membrane
Relay, transduction and amplification of message through secondary messengers
small (non-protein) molecules that relay signals from cell surface receptors to target
molecules within cell (through cytoplasm)
integration
distribution of message to effector proteins (metabolic enzyme, cytoskeletal enzyme,
transcription regulator)
causes cell response
o Molecular Switches (intracellular signal molecules)
turning off a signal is just as important as turning it on
Turn on: protein kinase (transfer phosphate group from ATP to phosphate)
Turning off: protein phosphatase (remove phosphate group)
each activation step in a cascade needs to be inactivated
Signalling by Protein Phosphorylation
activity of a protein regulated by phosphorylation depends on balance between
activities of its kinases and phosphatases many proteins regulated by phosphorylation are themselves kinases
o phosphorylation cascades
o Signal molecule binds to receptor, activating a relay molecule, which activates
protein kinase 1, which changes ATP to ADP, activating protein kinase 2, etc..
o Eventually activated protein, which causes cellular response
phosphorylation of proteins is not random
o serine / threonine kinases
phosphorylate hydroxyl groups of serine and threonine in particular
sequences
o tyrosine kinases
phosphorylate hydroxyl groups of tyrosine
Signalling by GTP binding proteins
switch from active to inactive state depending on whether they are bound to GTP or
GDP
once bound to GTP, they have intrinsic GTPase activity, and turn themselves off by
hydrolyzing GTP to GDP (lose phosphate group)
dissociation of GDP and replacement with a ‘fresh’ GTP is often in response to a signal
active form will activate downstream steps in the cascade
Turning on: GTP binding
Turning off: GTP hydrolysis
o Classes of Cell-surface Receptors
Ion Channel-Coupled Receptors
binding of ligand opens (or closes) ion channel
flow of ions (inward or outward) changes voltage across membrane
o ‘neurotransmitter-gated’ channels
o ‘ligand-gated’ channels
G-protein Coupled Receptors (GPCRs)
binding of ligand activates trimeric GTP-binding proteins (G-proteins), which in turn
activate an enzyme or ion channel in membrane to set off cascade
about half of all known drugs act via GPCRs
Activation of a G-Protein Coupled Receptor
o Signal molecule binds to G-coupled receptor
o Activation of trimeric G-protein
o Gα subunit exchanges GDP for GTP
o Separation of α and βγ subunits
Self-Inactivating
o α subunit activates target protein
o Hydrolysis of GTP by α subunit inactivates itself and causes it to dissociate from
target protein
o Inactive α subunit reassembles itself with βγ complex to re-form inactive G-
protein
Length of a G-protein signal
o which is as long as the Gα-subunit is bound to GTP (α and βγ subunits are free)
o normally it hydrolyzes GTP GDP within a few seconds and re-associates with
βγ-subunits
Consequences of disrupted the Gα-subunit function o cholera
bacterium produces toxin that enters intestinal cells and alters Gα
subunit
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