receptor regulation, receptor related diseases, desensitization, up regulation, down regulation, GPCRs

1. RECEPTOR REGULATION
AND RECEPTOR RELATED
DISEASES
Dr. Plessan Joy

2. RECEPTOR REGULATION
↓ Response
 Tolerance
 Tachyphylaxis
 Down regulation
 Desensitisation
↑ Response
 Up regulation
 Supersensitivity

3. Tolerance
 Reduction in responsiveness as a
consequence of continued drug
administration

4. Tachyphylaxis
 Rapid reduction in
responsiveness as a
consequence of drug
administration
 Eg; Nitroglycerin

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

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

13. 5. Physiological Adaptation
 reduction of drug effects due to
opposing homeostatic response

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’

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

20. SUPERSENSITIVITY
exaggerated response following
chronic reduction in receptor
stimulation

23.  Eg;
1. prolonged receptor blockade
2. chronic denervation supersenitivity
3. in cardiac ischemia
4. hyperthyroidism

24. Diseases Resulting from
Receptor Malfunction

25. Autoimmune
 Nicotinic cholinergic receptors 
myasthenia gravis
 Insulin receptors  insulin-resistant
diabetes mellitus
 TSH receptor  Grave’s disease
(activation)
 TSH receptor  Atropic thyroiditis
(blocking)

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

31. Gain-of-function mutations
 Activation in the absence of a ligand
(constitutive activity)
 Increased sensitivity to the receptor’s usual
agonist

32.  Germ line activating mutation of
Arginine vasopressin receptor 2
Increased constitutive activity
Nephrogenic syndrome of inappropriate
antidiuresis 
X-linked dominant

33.  Somatic mutations of TSH receptor
Increased constitutive activity 
Autonomous thyroid adenomas 