G-protein (Guanine nucleotide-binding proteins) Regulatory proteins Comprise of three subunits (γ),  subunits possess GTPase activity. G proteins belong to the larger group of enzymes called GTPases. Regaulate guanine nucleotides GDP, GTP. They bind and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). They are active 'on' when they are bound to GTP They are inactive ‘off' when they are bound to GDP

1. Pharmacodynamics-II
Drug Receptor interaction and the role of beta
blockers to elicit a response with focus on G-protein
coupled receptors
Dr. AWAIS IRSHAD

2. G-protein (Guanine nucleotide-binding proteins)
• Regulatory proteins
• Comprise of three subunits (γ),  subunits
possess GTPase activity.
• G proteins belong to the larger group of
enzymes called GTPases.
• Regulate guanine nucleotides GDP, GTP.
• They bind and hydrolyze guanosine triphosphate
(GTP) to guanosine diphosphate (GDP).
• They are active 'on' when they are bound to
GTP
• They are inactive ‘off' when they are bound
to GDP

3. Receptors in this family respond to agonists
by promoting the binding of GTP to the G protein alpha ( α ) subunit.
GTP activates the G protein and allows it, in turn, to activate the effector protein.
The G protein remains active until it hydrolyzes the bound GTP to GDP and returns to itsground
(inactive) state.

4. G-protein
• When the G-protein trimer (γ), binds to agonist-
occupied receptor , the -subunit dissociates &
is then free to activate an effector.
• Activation of the effector is terminated when the
bound GTP molecule is hydrolyzed to GDP which
allow -subunit to recombine with (γ) and returns
to its inactive state.

5. Targets for G-proteins
Ion channels
e.g. Ach acts upon muscarinic receptors in heart
(opening of K-channel), to decrease heart rate
Enzymes
To give Second messengers
• Adenyl cyclase enzyme (AC)
Cyclic AMP system(cAMP)
• Phospholipase C enzyme
Inositol phosphate system (IP3+DAG)
cAMP= cyclic adenosine monophosphate
IP3 = inositol triphosphate DAG= diacylglycerol

6. Type II receptors (G-Protein coupled
receptors)
Targets for G-proteins
Activation or inhibitions of ion channels or enzymes
↑ lipolysis & ↑ breakdown of glycogen to glucose
Adenyl cyclase
enzyme cAM
P
Phosphorylation of Protein kinase A
(PKA)
Active protein kinase A
•Second messengers
Cyclic AMP system
(cAMP)
ATP
G Protein

7. Type II receptors
Targets for G-
proteins
Inositol phosphate
system
Phospholipas
e C
Inositol triphosphate
IP3
Increase intracellular
calcium
Secretion of exocrine
glands Increase in heart
rate Smooth muscle
Phosphoinositol
diphosphate
(PIP2)
G Protein
Diacylglyce
rol
(DAG)
Protein
kinase C
(PKC)
Ion channels
Smooth
muscle
contraction

8. m Ach; m1, m2, m3, m4
 Adrenergic receptors; 
 
Type II receptrs (G-Protein-Coupled
Receptors)
AretheMostAbundant T
ype
Different Classes of Receptors
Different Receptors Subtypes
cholinergic R (Ach) m Adrenergic R (NA)
 & 
Difference in their related G-Protein Classes

9. G-protein
(Guanine nucleotide-binding proteins)
are divided according to their α-
subunits into: Gs: stimulation of the
effector
Linked to the cAMP-dependent pathway
Gi: Inhibition of the effector
Linked to the cAMP-dependent pathway
Gq (activation, linked to Inositol phosphate
system).

10. Ach receptors Couple to
M1 stimulatory Gq stimulate PLC stimulation
M2 inhibitory Gi Inhibit AC ( cAMP)
Opening of K-
channels
Heart (Bradycardia)
M3 stimulatory Gq stimulate PLC Contraction of Smooth
muscles
(brocnchoconstriction)
M4 inhibitory Gi Inhibit AC ( cAMP) Inhibition
Adrenoceptors Couple
to
1 stimulatory Gs stimulate AC Stimulation (tachycardia)
 1 stimulatory Gq stimulate PLC Contraction of smooth muscles

12. Continue
Activation and inhibition of adenylyl
cyclase
by agonists that bind to
catecholamine receptors.

13. Continue
Binding to B adrenoceptors stimulates adenylyl
cyclase
by activating the stimulatory G protein, Gs, which
leads to the dissociation of its α subunit charged
with GTP.

14. Continue
This activated αs subunit directly activates
adenylyl cyclase, resulting in an increased
rate of synthesis of cAMP.

15. Beta receptors
Activation of all three receptor subtypes B1, B2
and
B3 results in stimulation of adenylyl cyclase
and increased cAMP.

16. Activation of the cyclase enzyme is mediated by the
stimulatory
coupling protein Gs. Cyclic AMP is the major second
messenger of B-receptor activation.
Continue

17. Continue
In the heart, B-receptor activated cAMP synthesis
increases
the influx of calcium across the cell membrane
and its sequestration inside the cell.

18. Continue
Beta receptor activation also promotes the
relaxation of
smooth muscle.

19. Beta adrenoceptors may activate voltage sensitive calcium channels in the
heart via coupling to Gs but independent of cAMP.
under certain circumstances, β2 receptors may couple to Gq proteins.

20. Beta adrenergic blockingagents
Beta blockers are comitative antagonist of beta agonist
Propranolol is the prototype β- adenargic antagonist and blocks both
β1 and β2 receptors with equal affinity non selective beta blockers
including propranolol, have the ability to block the actions of
isoproterenol (β1 and β2 ) on the cardiovascular system.

21. Continue
Thus in the presence of a beta blocker, isoproterenol
does not produce cardiac stimulation (β1 mediated) or
reductions in mean arterial pressure and diastolic
pressure (β2 mediated)

22. References:
1. B G Katzung. Basic and clinical pharmacology, 14th edition
2. Lippincott illustrated reviews pharmacology, 7th edition
3. Katzung and Trevor's pharmacology examination and board review

23. Thank you
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