RECEPTOR REGULATION AND RECEPTOR RELATED

DISEASES

Dr. Plessan Joy

RECEPTOR REGULATION

↓ Response Tolerance Tachyphylaxis Down regulation Desensitisation

↑ Response Up regulation Supersensitivity

Tolerance

Reduction in responsiveness as a consequence of continued drug administration

Tachyphylaxis

Rapid reduction in responsiveness as a consequence of drug administration

Eg; Nitroglycerin

Down regulation

Decrease in no of receptors

receptor internalization and degradation

Eg;Beta2 agonist in asthma

Desensitization

After reaching an initial high response, the effect diminishes over seconds or minutes even in the continued presence of the agonist.

Reversible

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

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

2. Reduction of Receptor Number slower, long-term desensitization E.g: phosphorylation of specific amino

acids in GPCRs causes removal from cell surface

3. Reduction of Receptor-Coupled Signaling Components

depletion of signaling molecules Eg: prolonged stimulation of GPCRs

can lead to depletion of intracellular second messengers

4. Increased Metabolic Degradation of drugs

lowers drug concentrations Eg: barbiturates induce the

expression of cytochrome P450s

5. Physiological Adaptationreduction of drug effects due to

opposing homeostatic response

Series of events inOpiod Receptor desensitization

1. Acute signaling.

2. Rapid desensitization

3. Endocytosis

4. Post-endocytic sorting (i) ‘resensitization’. (ii) ‘down-regulation’

D D D D

αα

βα γ

(1) Agonist bindingand G protein

activation

(2) Phosphorylation

P P

(3) Arrestinbinding

ArrestinP P

Arrestin

P P

Clathrin(4) Clustering inclathrin-coated

pits

(5) EndocytosisEndosomes

ArrestinP P

D

(7) Recycling

(6) Dissociation of agonist:• Dephosphorylation• Sorting between cycling

and lysosomal pathways

(8) Traffic tolysosomes

Lysosomes

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

• An antagonist may increase thenumber 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

SUPERSENSITIVITYexaggerated response followingchronic reduction in receptor stimulation

Eg;

1. prolonged receptor blockade

2. chronic denervation supersenitivity

3. in cardiac ischemia

4. hyperthyroidism

Diseases Resulting from Receptor Malfunction

Autoimmune

Nicotinic cholinergic receptors myasthenia gravis

Insulin receptors insulin-resistant diabetes mellitus

TSH receptor Grave’s disease (activation)

TSH receptor Atropic thyroiditis (blocking)

Loss-of-function mutations

Loss of GPCR function is associated with hypophenotypes of the target tissues;

Hypothyroidism, hypogonadism, short stature, diabetes insipidus

1.Simple loss of function Eg; Melanocortin 2 receptor Familial glucocorticoid deficiency type 1 Autosomal Recessive

2.Loss of basal activity Eg; Ghrelin receptor Short stature

Autosomal Dominant

Gain-of-function mutations

Activation in the absence of a ligand (constitutive activity)

Increased sensitivity to the receptor’s usual agonist

Germ line activating mutation of

Arginine vasopressin receptor 2

Increased constitutive activityNephrogenic syndrome of inappropriate

antidiuresis X-linked dominant

Somatic mutations of TSH receptor Increased constitutive activity Autonomous thyroid adenomas