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u 3. Kinase-linked receptors
u Ion channels
u Voltage-gated ion channels
u Enzymes
u Transporters (carriers)
u Symports and antiports
Chemical messengers
Cellular
Types
Sensing
of receptor
element response
?
RECEPTOR
EFFECTOR LINKAGE
(Signal transduction
Copyright UTS, 2017 mechanisms) Slide 7 of 53
Receptor structure
uReceptors: An intracellular or cell-surface
protein with which a drug or a signalling
molecule interacts, to initiate a chain of
biochemical events in the cell or organism
uGlycine
20 membrane-
spanning alpha
helices
ACh binding
ACh binding
Structure of the nicotinic acetylcholine receptor (a typical ligand-gated ion channel).
side view (upper) and plan view (lower). The five receptor subunits (!2, ", #, $) form a clust
Copyright UTS, 2017 Slide 15 of 53
Nicotinic ACh receptor
- -
Na+ or K+
- -
Influx causes
- -
- -
depolarisation of
the cell
(sometimes Ca++)
"for their discovery of G-proteins and the role of these proteins in signal
transduction in cells"
Robert J. Lefkowitz
Brian K. Kobilka
USA USA
u Coupling: G-protein
uMuscarinic ACh
uAdrenoceptors
Receptor
Second Messenger
Cellular
Secondary Effector
response
Copyright UTS, 2017 Slide 26 of 53
2. G-protein coupled receptors 4
u G-proteins
u Involves intermediary G-proteins (Guanyl nucleotide-
binding protein) present in receptor-membrane complex
u G-proteins serve 3 roles
u 1.
G-proteins bind guanosine triphosphate (GTP) and GDP
G-proteins exist in 2 states:
u active form - GTP bound
u inactive form - GDP bound
u Targets for G-
proteins
u Adenylate cyclase/
cAMP system
u Phospholipase C/ Primary effector
inositol phosphate
system
u Regulation of ion
channels
Second messenger
Copyright UTS, 2017 Slide 30 of 53
cAMP is hydrolysed by
phosphodiesterases (PDE)
Cell specific (11 subtypes)
PDEs Can be inhibited for
example by caffeine
Protein
phosphorylation
AA = arachidonic acid
DAG = diacylglycerol,
Copyright UTS, 2017 IP3 = inositol triphosphate
Slide 31 of 53
Calcium vs. cAMP
Endoplasmic
reticulum
IP3
PKA
(protein kinase A)
u Coupling: direct
u Examples:
u Insulin
u Growth factors eg.
Epidermal growth factor
(EGF), nerve growth
factor, platelet derived
growth factor (PDGF)
u Cytokine receptors eg.
interferon-gamma (IFN-)
Binding of
SH2 domains
of adaptor
proteins
Activation of
transcription
factors
Copyright UTS, 2017 Slide 38 of 53
3. Kinase-linked receptors 4
<b>Transduction mechanisms of kinase-linked receptors.</b> The firnline Medical Textbooks Library for Students plus USMLE Steps 123 5/03/13 1:58 PM
u Insulin receptor is an
exception - it exists
as a dimer
u Receptor is
phosphorylated by
cytosolic kinases
u Phosphatidylinositol
3-hydroxy kinase
{PI(3)K}, makes
PIP2,PIP3
u Grb2, Sos, activates
Ras
u Activation of PI-PLC
Intracellular
DNA