Receptor desensitization and regulation of receptors,Diseases resulting from receptor and pathway dysfunction, Physiological systems Integrated multiple signals

1. Receptor desensitization and
regulation of receptors,
Diseases resulting from receptor
and pathway dysfunction,
Physiological systems Integrated
multiple signals
Presenter- Akash Agnihotri

2. Introduction
• Protein targets for drug action-
• Receptors
• Ion channels
• Enzymes
• Transporters (carrier molecules)
• Great majority of important drugs act on one or other of these
types of protein
• Exception is-
• Colchicine used to treat arthritic gout attacks interacts with structural
protein tubulin
• Immunosuppressive drugs (ciclosporin) bind to cytosolic proteins known
as immunophilins

3. Drug Targets
• Macromolecules
• Present either in plasma membrane or
cytoplasm
• Upon binding to a drug mediate those
biochemical and physiologic changes
• Selectively allow passage of particular
ions
• Two important types are ligand-gated
channels and voltage-gated channels.
• Drugs binding to the ion channel-
• Dihydropyridine- inhibit opening of L-type
calcium channels
• Sulfonylureas- ATP-gated potassium
channels
Drug Targets

4. Drug Targets
• Many drugs are targeted on enzymes
• Drug molecule is substrate analogue that
acts as a competitive inhibitor of the
enzyme (captopril, acting on angiotensin-
converting enzyme)
• In other cases, binding is irreversible and
non-competitive
• Movement of ions and small organic
molecules across cell
• By Channels or Transport proteins
• To penetrate lipid membranes on their
own

5. Regulation of Receptors
Up
Regulation
• Cell increase quantity of cellular component
↑ Response
Supersensitivity
Down
Regulation
• Cell decrease quantity of cellular component In response to
external variable
↓ Response
Tolerance
Tachyphylaxis
Desensitisation

6. Supersensitivity
• Condition in which sensitivity of receptor to agonist increases to
a chronic reduction of receptor stimulation
• This can result of withdrawal of prolonged receptor by use of
antagonist
• E.g: after rapid termination of a long-term treatment with β-
adrenergic receptor blockers
• It can be result from:
• Unmasking of receptors
• Synthesis and recruitment of new receptors (up regulation)

7. Tolerance
• Reduction in responsiveness (consequence of continued drug
administration)
• Taking hours, days or weeks to develop, but distinction is not a sharp
one
• Clinically, a higher dose is required to obtain the original response
Tachyphylaxis
• Rapid reduction in responsiveness as a consequence of drug
administration
• Transmitter depletion and receptor desensitization are basic
mechanismsof this phenomenon
• E.g, Nitroglycerin

8. Receptor Desensitization
• Receptors are almost always subject to feedback regulation by
their own signaling outputs
• Often, effect of a drug gradually diminishes when it is given
continuously or repeatedly
• Desensitisation and tachyphylaxis are synonymous terms used
to describe this phenomenon, which often develops in course of
a few minutes

9. Receptor
Desensitization-

10. Receptor Desensitization
• Continued stimulation of cells with agonists- desensitization
(also referred to as adaptation, refractoriness, or
downregulation)
• Effect of continued or repeated exposure to same concentration
of drug is diminished
• Receptor desensitization summarizes pharmacodynamic
processes that lead to an inactivation of receptor signaling
within seconds to minutes

11. Rapid desensitization, resensitization, and
down-regulation of β adrenoceptors

12. Rapid desensitization, resensitization, and down-regulation of β adrenoceptors

13. • Phosphorylation of GPCRs by specific GRKs plays a key role in
triggering rapid desensitization
• Phosphorylation of agonist-occupied GPCRs by GRKs
facilitates the binding of cytosolic proteins termed arrestins to
receptor, resulting in uncoupling of G protein from receptor
• β arrestins recruit proteins, such as PDE4, which limit cAMP
signaling- promote sequestration of receptor from membrane
(internalization)
• Visual arrestin 1 and arrestin 4 and the ubiquitously expressed
arrestins 2 and 3 (also known as β-arrestin-1 and β-arrestin-2) –
can be distinguished

14. Mechanism of receptor desensitization
Two types of receptor desensitization-
• Homologous desensitization
• Heterologous desensitization

15. Homologous desensitization
• Effects of agonists at only one type of receptor are diminished
• The so-called G protein-coupled receptors kinases (GRKs) are
responsible for homologous agonist-induced receptor
phosphorylation.
• So far, 7 GRKs have been cloned.
• Expression of GRK1 and -7 is confined to retinal rods and
cones, respectively
• GRK2,-3,-5, and -6 are most widely distributed GRKs, but
expression and knockout studies also implicate more distinct
roles of individual GRKs

16. Heterologous desensitization
• Effects of agonists at two or more types of receptors are
coordinately diminished
• Heterologous desensitization is thought to be caused by drug-
induced alteration in a common point of convergence in signaling
pathways activated by the involved receptors
• Prolonged activation of one type of GPCRs causes
desensitization of all GPCRs ↓Second messenger or
Nonselective phosphorylation

17. Mechanisms of
receptors regulation

18. Diseases Resulting From Receptor
and Pathway Dysfunction
• The principal mechanisms involved are:
• autoantibodies directed against receptor proteins
• mutations in genes encoding receptors, ion channels and proteins
involved in signal transduction
• E.g: Myasthenia gravis (neuromuscular junction) due to
autoantibodies that inactivate nicotinic acetylcholine receptors
Autoantibodies can also mimic the effects of agonists
• As in many cases of thyroid hypersecretion, caused by
activation of thyrotropin receptors

19. Diseases Resulting From Receptor
and Pathway Dysfunction
• Activating antibodies have also been discovered in patients
with-
• Severe hypertension (α adrenoceptors)
• Cardiomyopathy (β adrenoceptors)
• Certain forms of epilepsy and neurodegenerative disorders (glutamate
receptors)

20. Diseases Resulting From Receptor
and Pathway Dysfunction
• Mutations in G proteins can also cause disease
• For example, mutations of a particular Gα subunit cause one
form of hypoparathyroidism
• Mutations of a Gβ subunit result in hypertension
• Many cancers are associated with mutations of the genes
encoding growth factor receptors, kinases and other proteins
involved in signal transduction

21. Diseases Resulting From Receptor
and Pathway Dysfunction
• Mutations in ligand-gated ion channels (GABAA and nicotinic)
and other ion channels (Na+ and K+) that alter their function
give rise to some forms of idiopathic epilepsy

22. Diseases Resulting From Receptor
and Pathway Dysfunction
• Alteration in receptors and their downstream signaling pathways
can be the cause of disease
• Loss of a receptor in a highly specialized signaling system may
cause a phenotypic disorder (e.g., deficiency of the androgen
receptor and testicular feminization syndrome)
• Deficiencies in widely employed signaling pathways have broad
effects, as are seen in myasthenia gravis (due to autoimmune
disruption of nicotinic cholinergic receptor function)
• In some forms of insulin-resistant diabetes mellitus (as a result
of autoimmune depletion of insulin and interference with insulin
receptor function)

23. Diseases Resulting From Receptor
and Pathway Dysfunction
• Common polymorphisms in receptors and proteins downstream
of the receptor can also lead to variability in therapeutic
responses in patient populations from different geographic and
ethnic origins
• Americans is attributable to polymorphisms in several
components of the myocardial β adrenergic receptor signaling
pathway, including β1 adrenergic receptor polymorphisms that
increase its constitutive activity and sensitivity to activation by
NE

24. Diseases caused by
GPCR loss of
function mutations-

25. Disease related with GRK2
expression
• Role of GRK2 in cardiac failure-
• Abnormalities in GPCR receptor signaling pathways results in severe
symptoms of heart failure
• Animal models of heart disease shows Upregulation of GRK2
expression
• Proven by experiments:
• GRK2 over expression
• GRK2 inhibition

26. Physiological Systems
Integrate Multiple Signals

27. Physiological Systems
Integrate Multiple Signals-

28. Extracellular signaling molecules
• Critical regulators of physiology and development in organisms
• There are many different types of signals:
• Peptides
• Small lipophilic molecules
• Small hydrophilic molecules
• Binding of extracellular signaling molecules to cell surface
receptors trigger intracellular pathways that ultimately modulate
cellular metabolism, function, or development

29. Intracellular signaling molecules
• Relays signals received at receptors, ultimately results in
signaling cascade
• It transduce and integrate signals before relaying a signal
forward
• Intracellular signaling complexes enhance speed, efficiency and
specificity of response

31. Physiological Systems Integrate
Multiple Signals
• As a consequence of the variety of pathways that affect arteriolar tone,
a patient with hypertension may be treated with one or several drugs
that alter signaling through these pathways.
• Drugs commonly used to treat hypertension-
• β1 adrenergic receptor antagonists
• To reduce secretion of renin (the rate-limiting first step in AngII
synthesis);
• Direct renin inhibitor (aliskiren)
• To block the rate-limiting step in AngII production;
• ACE inhibitors (enalapril)
• To reduce the concentrations of circulating AngII;
• AT1R blockers (losartan)

32. Physiological Systems Integrate
Multiple Signals
• Thus, choices and mechanisms are complex, and the
appropriate therapy in a given patient depends on many
considerations, including
• Diagnosed causes of hypertension in patient,
• Possible side effects of the drug
• Efficacy in a given patient
• Cost

33. References
1. The pharmacological basis of therapeutics, 13th edition by
Goodman & gillman’s
2. Basic and Clinical pharmacology, 13th edition by B.G. Katzung
3. Principle of pharmacology- The Pathophysiologic Basis of
Drug Therapy, 4th edition, by David E. Golan, Ehrin J. and
April W.
4. Rang and Dale’s Pharmacology, 8th edition
5. Schoneberg, T. (n.d.). Tolerance and Desensitization.
Encyclopedia of molecular pharmacology. 1203-1207.
DOI: https://doi.org/10.1007/978-3-540-38918-7_140

34. Thank you