L13 Broad Principles of Cell Signalling

what is cell signalling important for?

the transfer of information (communication) from cell to cell

what does communication enable cells and tissues to do

react, altering their behaviour and maintaining homeostasis

give an example of how cell signalling affects metabolism

control of blood-glucose levels

give an example of how cell signalling affects the nervous system

• electrical signalling

• synaptic signalling

give an example of how cell signalling affects the cell cycle

prevention of cancer

give an example of how cell signalling affects development

• cellular differentiation

• growth

• sex determination

give an example of how cell signalling affects physiology

• muscle contraction

• lung function

• water balance

give an example of how cell signalling affects pharmacology

control of cell function by pharmaceuticals

give an example of how cell signalling affects immunology

recruitment of white blood cells

give examples of physical signals cells are able to respond to

• light

• heat

• pressure

what does about 10-15% of the genome of eukaryotic cells code for

signalling molecules

cells decode the ‘signal-receptor’ interaction (reception) to…

produce a ‘response’ from the target cell/tissue

what are 5 methods of cell-to-cell communication

• gap junctions

• autocrine and paracrine signals

• hormone

• neurotransmitter

• neurohormone

list the signal processing pathway

• chemical signal

• receptor

• transducer

• amplifier

• 2nd messenger

• effectors

• response element

• response

what are the components for a chemical signal

• pheromones

• hormones

• local hormones

• neurotransmitters

• cell surface molecules

what are the components for a receptor

• ion channel-linked

• G protein-linked

• tyrosine kinase-linked

what are the components for a transducer

• G-proteins

• non-receptor tyrosine kinases

what are the components for an amplifier

• adenylyl cyclase

• phospholipase C

what are the components for a 2nd messenger

Cyclic AMP, InsP3 (IP3), Ca2+, DAG, proteins

what are the components for effectors

• protein kinases

• Ca2+ binding proteins (eg calmodulin, troponin C)

what are the components for a response element

• enzymes

• ion channels

• transcription factors

what are the components for a response

• metabolism

• secretion

• contraction

• excitability

• gene transcription

• cell growth

what are the components used in the cAMP to CFTR pathway

• hormones

• G-protein-linked

• G-proteins

• Adenylyl cyclase

• Cyclic AMP

• Protein kinases

• ion channels

• secretion

what is amplification

a single hormone-receptor interaction can be amplified by up to 10^6

describe heterogeneity -the concept of diversity

each pathway component often has multiple forms and cells can mix and match components

describe information transfer

information is passed from one component to the next using 2 basic mechanisms

describe dynamics

responses are dependent on both temporal and spatial aspects of the signalling components

list the steps of amplification - the cAMP signalling cascade

• signal binds to a G protein-linked receptor which activates the G protein

• G protein turns on adenylyl cyclase, an amplifier enzyme

• adenylyl cyclase converts ATP to cyclic AMP

• cAMP activates protein kinase A

• protein kinase A phosphorylates other proteins, leading to a cellular response

give examples of Galpha responses of heterogeneity

• InsP3

• DAG

• Cyclic AMP

• Cyclic GMP

• Cytoskeleton

give examples of Gbeta responses of heterogeneity

• cytoskeleton

• PIP3

• delta V increase

• Ca2+ decrease

• Cyclic AMP

information transfer creates a …

• confomational change

• covalent modification

give examples of information transfer

• chemical signal to receptor

• receptor to G-protein

• G-protein to amplifier

• 2nd messenger to protein kinase

describe how a conformational change occurs

• G-proteins transduce signals by binding to other proteins on the plasma membrane

• after a short delay, G-proteins turn themselves off by GTP-hydrolysis

• G-proteins act as molecular switches

give an example of a covalent modification

phosphorylation

• protein kinase to protein kinase

• protein kinase to response element

define phosphorylation

addition of the terminal phosphate group of ATP to a hydroxyl (OH) group of specific amino acid(s) within a target protein, by a protein kinase (PK)

what will the PK only phosphorylate residues that lie within

a specific PK

• consensus motif

what are the most common residues phosphorylated in mammalian cells

• serine

• threonine

• (tyrosine is less common)

phosphorylation changes…

the activity (or function) of the protein

how is phosphorylation reversed

dephosphorylation of the target residue(s) by protein phosphatases (PP)

cAMP passes information down the signalling pathway by activating cAMP dependent protein kinase (PKA)

• cAMP binding to PKA induces a conformational change

• This causes the release and activation of the catalytic subunits

what does PKA type II form a stable interaction with

AKAPs

what does PKA type II form a stable interaction with AKAPs via

R subunits

• not free in the cytosol

PKA type I is…

free in the cytosol

when cAMP binds to R subunits of PKA type II, the catalytic subunits are…

NOT released

when cAMP binds to R subunits of PKA type I, the catalytic subunits are…

released

the dynamics of the temporal response is decoded by the cell to produce…

distinct downstream responses

what does stimulation of cardiac cells by noradenaline (NE) lead to

spatial differences in cAMP levels in different parts of the cell

different agonists produce distinctive spatial responses, which are decoded into…

different ‘functional’ outputs from the cells