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RECEPTOR  DESENSITIZATION Varun m. mehta Department of pharmacology M.Pharm-I (2008-09)
CONTENTS ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
RECEPTOR DESENSITIZATION ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
   ->  After exposure to an agonist, the  initially maximum response  is seen.  ->  Now  if we continue to administer agonist it shows decrease in response due to desensitization of receptors.  ->  Removal of the drug for a more extended period allows the cell to recover its capacity to respond.
Types of Desensitization ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
->  When agonist is administered continuously,desensitization of the receptor  results ;  when agonist  falls below a certain threshold,the system again becomes sensitive. ->  E.G.  Think of whathappens to your visual transduction system when you walk from bright sunlight into a darkened room or from darkness into the light. Lehninger principles of biochemistry 4th Edition pg.427
Five ways by which target cells can become desensitized to a signal molecule. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.2792
Many factors can give rise to phenomenon of desensitization. ,[object Object],[object Object],[object Object],[object Object],[object Object]
1. Change in receptors ,[object Object],[object Object],[object Object],Acetylcholine (ACh) at the frog motor endplate. ->  Initially brief depolarisations (upward deflections) are produced by short pulses of ACh delivered from a micropipette.  ->  A long pulse (horizontal line) causes the response to decline, which shows the ionic receptor desensitisation, and it recovers with a similar time course. In Nut Shell Conformational change in receptor leads to receptor desensitisation.
2.LOSS OF RECEPTORS  ,[object Object],->  β-Adrenoceptors of rat glioma cells in tissue culture.  Isoprenaline (1μmol/l) was added at time zero, the response and β-adrenoceptor density measured at intervals. During the early phase, the response (blue line) declines with no change in receptor density (red line).  Later, the  response declines further concomitantly with disappearance of receptors from the membrane by internalisation. The green and orange lines show the recovery of the response and receptor density after the isoprenaline is washed out.  In Nut Shell Loss of receptor due to intenalisation lead to receptor desensitisation.
3.EXHAUSTION OF MEDIATORS ,[object Object],[object Object],In Nut Shell Depletion  of an essential mediators lead to receptor desensitisation.
4.ALTERED DRUG METABOLISM ,[object Object],[object Object],In Nut Shell Increased metabolic degradation of drugs lead to receptor desensitisation.
5.PHYSIOLOGICAL ADAPTATION ,[object Object],[object Object],In Nut Shell Drug effect may be nullified by homeostatic mechanism which may lead to receptor desensitisation.
Desensitization can be the result of ,[object Object],[object Object],[object Object],[object Object]
Mainly receptors can be desensitized in three different ways. ,[object Object],[object Object],[object Object],http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=eurekah.section.59454
General Mechanism of Agonist mediated Desensitization ,[object Object],[object Object],[object Object],[object Object],[object Object]
Steps involved in Agonist-induced internalization of GPCRs. ,[object Object],[object Object],[object Object],[object Object],[object Object]
Encyclopedic Reference of Molecular Pharmacology  pg. no. 913
[object Object],[object Object]
Desensitization of the  β  –adrenergic  receptor in the continued presence of epinephrine.  This process is mediated by two proteins: - Β - adrenergic protein kinase  (ARK)  &  β -arrestin (arr ; arrestin 2). Lehninger principles of biochemistry 4th Edition pg.440
Anti receptor antibody(ARAs) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],http://medical-dictionary.thefreedictionary.com/anti-receptor+antibody
Stress induced desensitization ,[object Object],[object Object],[object Object],[object Object]
Continued …….. ,[object Object],[object Object],[object Object],[object Object]
β -arrestins ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],http://jcs.biologists.org/cgi/reprint/120/2/213 Journal of Cell Science
Domain Structure of  β -arrestin ,[object Object],[object Object],[object Object],[object Object],[object Object],http://jcs.biologists.org/cgi/reprint/120/2/213 Journal of Cell Science
DISEASE RELATED WITH GRK2 EXPRESSION ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Continued…… ,[object Object],[object Object],[object Object],[object Object]
(2) Role of GRK2 in Hypertension ,[object Object],[object Object],[object Object]
Conclusion ,[object Object],[object Object]
How receptor  internalization can be studied? ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
(1) Transfluor Technology Cell-Based Fluorescence Technology for GPCRs ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Video recording of  Transfluor Technology
live-imaging of tagged adenosine receptors. ,[object Object],[object Object],(1) 0 minutes (2) 12 min. (3) 24 min. (4) 36 min. Department of Phsyiology & Pharmacology Receptor Biology & SignalingKarolinska Institutet, Stockholm
imaging of endogeneous adenosine receptors internalization  Department of Phsyiology & Pharmacology Receptor Biology & SignalingKarolinska Institutet, Stockholm
High-Throughput Screening ,[object Object],APPLICATIONS:- Use to study (1) Ligand binding,  (2) Receptor activation and  desensitization,
REFERENCES  ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Molecular Pharmacology-Receptor Desensitization

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Molecular Pharmacology-Receptor Desensitization

  • 1. RECEPTOR DESENSITIZATION Varun m. mehta Department of pharmacology M.Pharm-I (2008-09)
  • 2.
  • 3.
  • 4. -> After exposure to an agonist, the initially maximum response is seen. -> Now if we continue to administer agonist it shows decrease in response due to desensitization of receptors. -> Removal of the drug for a more extended period allows the cell to recover its capacity to respond.
  • 5.
  • 6. -> When agonist is administered continuously,desensitization of the receptor results ; when agonist falls below a certain threshold,the system again becomes sensitive. -> E.G. Think of whathappens to your visual transduction system when you walk from bright sunlight into a darkened room or from darkness into the light. Lehninger principles of biochemistry 4th Edition pg.427
  • 7. Five ways by which target cells can become desensitized to a signal molecule. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.figgrp.2792
  • 8.
  • 9.
  • 10.
  • 11.
  • 12.
  • 13.
  • 14.
  • 15.
  • 16.
  • 17.
  • 18. Encyclopedic Reference of Molecular Pharmacology pg. no. 913
  • 19.
  • 20. Desensitization of the β –adrenergic receptor in the continued presence of epinephrine. This process is mediated by two proteins: - Β - adrenergic protein kinase (ARK) & β -arrestin (arr ; arrestin 2). Lehninger principles of biochemistry 4th Edition pg.440
  • 21.
  • 22.
  • 23.
  • 24.
  • 25.
  • 26.
  • 27.
  • 28.
  • 29.
  • 30.
  • 31.
  • 32. Video recording of Transfluor Technology
  • 33.
  • 34. imaging of endogeneous adenosine receptors internalization Department of Phsyiology & Pharmacology Receptor Biology & SignalingKarolinska Institutet, Stockholm
  • 35.
  • 36.