Regulation of acetylcholine receptor gene expression in human ...
Receptor regulation and diseases
-
Upload
plessan -
Category
Health & Medicine
-
view
42 -
download
1
Transcript of Receptor regulation and diseases
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