Receptors

Receptor-Response Theory has 3 stages:

1) Reception 2) Signal Transduction (Pathway) 3) Response

Receptor Tyrosine Kinases (RTK)

Steps in Signalling Cascade:

1) Signalling molecule (ligand) 3) Autophosphorylation: each

2) Two tyrosine phosphorylates the
binds to the extracellular
bound tyrosine adjacent to it by
hydrophobic binding site (N
monomers converting ATP to ADP.
terminal) of each tyrosine
dimerise.
kinase monomer. Receptor is now active.

4) Adapter molecule binds to a phosphotyrosine at its SH2 domain and binds to the proline
molecule of an intracellular signalling molecule at its SH3 domain.
5) The signalling molecule then binds to inactive Ras (small GTPase) and converts it to active
Ras by exchanging its GDP for GTP. The signalling molecule then dissociates from active Ras.
6) Active Ras binds to effector molecules and initiates several different pathways such as
changes in protein activity and gene
expression.
Structure of Receptor:
Extracellular domain: binding site of ligand.
Intracellular tyrosine kinase domain: responsible for
transmitting signal when ligand bound
Role in growth factor signalling. Growth receptor
binding protein 2 (Grb2) is an adapter protein

Ligand-Gated Ion Channel-Linked Receptors

1) Ligand/Hormone binds to receptor and causes conformational change that opens the
channel in milliseconds. Ion influx.

Structure of Receptor:
 Membrane receptor coupled directly to an
ion channel
 E.g. Neurotransmitters
Nuclear (Intracellular) Receptors

1) Signalling molecule (ligand) enters

cell and binds to receptor to form
receptor-ligand complex which
causes receptor to release
chaperone it was bound to.
2) Receptor-ligand complex
translocates into cell nucleus.
3) Receptor’s DNA binding site binds
to specific genomic regions to alter
transcription levels essentially
changing cell gene expression
profile.

Structure of Receptor:
 a hormone binding site (to bind to
ligand and chaperone)
 a DNA binding site (to interact with
defined sites in genome)

E.g. glucocorticoid receptor – responds to cortisol

G-Protein Coupled Receptors

Structure:

 Passes through membrane 7 times.

 N terminal is extracellular.
 Number of loops on either side is
equal.
 Monomeric proteins MW 35K-70K
 Include light, taste and smell
receptors and neurotransmitters.

G-proteins:
 Enzymes composed of 3 subunits:
, ,  (heterotrimeric)
 Bind to and hydrolyses GTP to GDP
 Inactive when GDP bound
 Active when GTP bound
 Acquires high affinity for GTP when
associated receptor is activated
 The activity status of G proteins is
determined by the  subunit
 4 families of G proteins based on structural
similarities
 Gs, Gi, Gq and G12
 Main purpose is to regulate amplifier or
effector protein activity
 βγ exist as dimers and have no enzymatic
activity
 6 different β and 11 different γ
 Can also exert signalling activity
Method of Action:

Before Activation:
 The  and  of the G-protein anchor it to the membrane in its “inactive” or
“unbound” state
 G-protein is not linked to the receptor
 G-protein has GDP-bound

Ligand Binding and Activation:

 Receptor ligand binds to GPCR
 The occupied receptor couples with the -subunit
 GDP is replaced with GTP

Signal Generation:
 -GTP is the “active” form of the receptor
 -GTP complex dissociates from the receptor to interact with the effector enzyme

Effectors/Amplifiers/Enzymes:

1) Adenylate Cyclase

When adenylate cyclase activity is disrupted:

 Covalent modification of Gas - can’t hydrolyse ATP (locked ‘ON’)
 Elevated cAMP levels in colonic epithelium cause efflux of water and ions - severe
diarrhea and dehydration
Treatment:
 Loperamide/Imodium acts as an opioid receptor agonist in large intestine
 Treatment – opiate receptor coupled to Gi
 Through Gi, opium antagonizes the out of control Gs
 2) Phospholipase C

Switching Off Signalling:

 The GTPase activity of the -

subunit is increased when the
effector protein is bound
 This causes hydrolysis of bound
GTP to GDP
 GDP-bound -subunit re-unites
with the  complex