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Slide 1
 G-protein Coupled
Receptors (GPCRs)
Module 6 – Signals dictate Cellular Decisions

Dr James Tsatsaronis

Department of Biochemistry and Genetics Slide 2

Intended Learning Outcomes
(ILOs)
After this lesson students will be able to:
• Outline four signal transduction receptor systems
• Describe the function, outcome and sequence of events in
the β-adrenergic signalling system
• Explain how signalling amplification and desensitisation is
achieved within the β-adrenergic signalling system

Slide 3
Types of signal transduction
systems
• All signal transduction systems have receptors that
recognise a signal, activating signalling machinery
which works on effector proteins
• Four generic types of receptors can be
distinguished:
• G protein-coupled receptors (GPCRs)
• Receptor enzymes
• Gated ion channels
• Nuclear receptors

Slide 4
Types of membrane receptor

Slide 5
G Protein-Coupled Receptor
(GPCR) signalling
• GPCR signalling involved in allergies, depression,
blindness, diabetes and many common conditions
• GPCRs act through a GTP-binding protein (G protein)
• Essentially include:
1. The plasma membrane bound GPCR
2. A G protein that cycles between active (GTP-bound) and
inactive (GDP-bound) forms
3. An effector enzyme which is controlled by the activated G
protein

Slide 6
G Protein-Coupled Receptor
(GPCR) signalling
1. A signal (“first messenger” which is a hormone, growth factor or other
factor) binds GPCR
2. GPCR is activated and the associated G protein exchanges GDP for
GTP from the cytosol
3. G protein disassociates from the GPCR and binds the effector enzyme,
altering its activity
4. Downstream change in metabolite or ion from the effector known as a
“second messenger”

Slide 7
 G Protein-coupled Signalling
• G protein−coupled receptors (GPCRs) are α-helical
integral membrane proteins
• G-proteins are heterotrimeric (αβγ) membrane-associated
proteins that bind GTP.
• G-proteins mediate signal transduction
from GPCRs to other target proteins
• GPCRs include β-adrenergic
receptors

Slide 8
β-Adrenergic Receptor System

• Epinephrine (adrenaline): hormone synthesised in adrenal

glands (pair of organs on top of kidneys)
• Mediates stress response (mobilisation of energy)
• Binding to receptors in muscle or liver cells induces
breakdown of glycogen
• Binding to receptors in adipose cells induces lipid hydrolysis
• Binding to receptors in heart cells increases heart rate

Slide 9
β-Adrenergic Receptor System

Slide 10
Self-Inactivation Mediates
Desensitization in G-protein Signalling
• Epinephrine is meant to be a
short-acting signal.
• The organism must stop
glucose synthesis if there is no
more need to fight or flee.
• Down-regulation of cAMP occurs
by the hydrolysis of GTP in the α
subunit of the G-protein.

Slide 11
 Signal Amplification
in Epinephrine Cascade
• Activation of a few GPCRs leads to
activation of few adenylyl cyclase
enzymes
• Each active adenylyl cyclase enzyme
makes several cAMP molecules;
activating several PKA enzymes
• These activate thousands of
glycogen-degrading enzymes in the
liver tissue
• At the end, tens of thousands
of glucose molecules are
released to the bloodstream

Slide 12
Summary
• There are four generic types of membrane receptors in
signalling systems
• GPCR systems bind G proteins which activate downstream
membrane proteins and generate secondary messengers
• The β-adrenergic signalling system is activated by
epinephrine and activates cAMP-dependent protein kinase
(protein kinase A or PKA), which utilises cAMP as a
secondary messenger
• Intrinsic GTP hydrolysis inactivates G protein, acting as a
self limiting binary switch
• Epinephrine binding sets off a signalling cascade, with
amplification through every step of the system, resulting in a
exponentially larger physiological response
Slide 13
Resources

• Lehninger Principles of Biochemistry Seventh Edition

(2017), W. H. Freeman and Company
• Chapter 12.1 – 12.2

• Molecular Biology of the Cell Sixth Edition (2015), Garland

Science
• Chapter 15

Slide 14