5. Down regulation
Decrease in no of receptors
receptor internalization and degradation
Eg;Beta2 agonist in asthma
6. Desensitization
After reaching an initial high response, the
effect diminishes over seconds or minutes
even in the continued presence of the
agonist.
Reversible
7.
8. Mechanisms of
Desensitisation
1. Loss of Receptor Function
2. Reduction of Receptor Number
3. Reduction of Receptor-Coupled Signaling
Components
4. Increased Metabolic Degradation of drugs
5. Physiological Adaptation
9. 1. Loss of Receptor Function
Rapid
Due to change in receptor conformation
Eg; phosphorylation of specific amino
acids in GPCRs blocks coupling to G-
proteins
10. 2. Reduction of Receptor Number
slower, long-term desensitization
E.g: phosphorylation of specific amino
acids in GPCRs causes removal from
cell surface
11. 3. Reduction of Receptor-Coupled
Signaling Components
depletion of signaling molecules
Eg: prolonged stimulation of GPCRs
can lead to depletion of intracellular
second messengers
12. 4. Increased Metabolic Degradation of
drugs
lowers drug concentrations
Eg: barbiturates induce the
expression of cytochrome P450s
14. Series of events in
Opiod Receptor desensitization
1. Acute signaling.
2. Rapid desensitization
3. Endocytosis
4. Post-endocytic sorting
(i) ‘resensitization’.
(ii) ‘down-regulation’
15.
16. D D D D
α
α
β
α γ
(1) Agonist binding
and G protein
activation
(2) Phosphorylation
P P
(3) Arrestin
binding
Arrestin
P P
Arrestin
P P
Clathrin(4) Clustering in
clathrin-coated
pits
(5) EndocytosisEndosomes
Arrestin
P P
D
(7) Recycling
(6) Dissociation of agonist:
• Dephosphorylation
• Sorting between cycling
and lysosomal pathways
(8) Traffic to
lysosomes
Lysosomes
17. Types of desensitization
Homologous
Prolonged
activation of one
type of GPCRs
causes
desensitization of
that receptor only
βARK, β arrestin
binding
Heterologous
Prolonged
activation of one
type of GPCRs
causes
desensitization of
all GPCRs
↓Second
messenger or
nonselective
phosphorylation
18. • An antagonist may increase the
number of receptors
by preventing downregulation caused
by an endogenous agonist.
• When the antagonist is withdrawn
the elevated number of receptors can
produce an exaggerated response..
Receptor Upregulation
26. Loss-of-function mutations
Loss of GPCR function is associated with
hypophenotypes of the target tissues;
Hypothyroidism, hypogonadism, short
stature, diabetes insipidus
27. 1.Simple loss of function
Eg; Melanocortin 2 receptor
Familial glucocorticoid deficiency type 1
Autosomal Recessive
28. 2.Loss of basal activity
Eg; Ghrelin receptor Short stature
Autosomal Dominant