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PHARMACOLOGY OF RECEPTORS:
STRUCTURAL AND FUCTIONAL
FAMILIES
Dr. Santosh M.
CONTENTS IN BRIEF
 1) Types of receptors
 2) Cytoplasmic secondary messengers
 3) Regulation of receptors
 4) Drug receptor interaction
 5) Diseases resulting from receptor malfunctioning
 6) Significance of receptor subtypes
BRIEF INTRODUCTION
 The relatively small number of biochemical mechanisms and
structural formats used for cellular signaling is fundamental to the
ways in which target cells integrate signals from multiple receptors
to produce additive, sequential, synergistic, or mutually inhibitory
responses.
 The regulatory actions of a receptor may be exerted directly on its
cellular target(s), effector protein(s), or may be conveyed by
intermediary cellular signaling molecules called transducers.
TYPES OF RECEPTORS
 1)Receptors as Enzymes: Receptor Protein Kinases and
Guanylyl Cyclases:
 exert their regulatory effects by phosphorylating diverse effector proteins at the
inner face of the plasma membrane.
 Most receptors that are protein kinases phosphorylate tyrosine residues in their
substrates. Eg: Insulin
 are composed of an agonist-binding domain on the extracellular surface of the
plasma membrane, a single membrane-spanning element, and a protein kinase
domain on the inner membrane face.
 For the receptors that bind atrial natriuretic peptides and the peptides guanylin and
uroguanylin, the intracellular domain is a guanylyl cyclase that synthesizes the
second messenger cyclic guanosine monophosphate (cyclic GMP), which activates
a cyclic GMP–dependent protein kinase (PKG) and can modulate the activities of
several cyclic nucleotide phosphodiesterases, among other effectors. Eg: ANP,
BNP
ILLUSTRATION-
TYPES OF RECEPTORS:
 2)Protease Activated Recptor signaling: Proteases that are
anchored to the plasma membrane or that are soluble in the extracellular
fluid(e.g. thrombin) can cleave ligands or receptors at the surface of cells to
either initiate or terminate signal transduction.
Eg: ACE inhibitors used for treatment of hypertension
 3) Ligand gated ion Channels: These are most important
Receptors for several neurotransmitters form agonist-regulated ion-
selective channels in the plasma membrane, termed ligand-gated ion
channels or receptor operated channels, that convey their signals by
altering the cell’s membrane potential or ionic composition.
 Eg: Acetyl Choline, Serotonin, GABA etc.
ILLUSTRATION:
TYPES OF RECEPTORS:
 4) G Protein Coupled Receptors:
G proteins are signal transducers that convey information (i.e., agonist
binding) from the receptor to one or more effector proteins. GPCRs include
diverse group of biogenic amines, eicosanoids and other lipidsignaling
molecules, peptide hormones, opioids, amino acids such as GABA, and
many other peptide and protein ligands.
 Because of their number and physiological importance, GPCRs are the
targets for many drugs; perhaps half of all nonantibiotic prescription drugs
are directed toward these receptors that make up the third largest family of
genes in humans.
 Central to the effect of many GPCRs is release of Ca2+ from intracellular
stores.
ILLUSTRATION:
TYPES OF RECEPTORS:
 5) Transcription Factors:
 Receptors for steroid hormones, thyroid hormone, vitamin D, and the
retinoids are soluble DNAbinding proteins that regulate the transcription of
specific genes.
 Regulatory sites in DNA where agonists bind are receptor-specific: the
sequence of a “glucocorticoid-response element,” with only slight variation, is
associated with each glucocorticoid-response gene, whereas a “thyroid-
response element” confers specificity of the actions of the thyroid hormone
nuclear receptor.
TYPES OF RECPTORS:
 6) Cytoplasmic second messengers:
 Binding of an agonist to a receptor provides the first message in
receptor signal transduction to effector to affect cell physiology. The
first messenger promotes the cellular production or mobilization of a
second messenger, which initiates cellular signaling through a
specific biochemical pathway.
 Eg: cyclic AMP, cyclic GMP, cyclic ADP–ribose, Ca2+, inositol
phosphates, diacylglycerol, and nitric oxide (NO).
REGULATION OF RECEPTORS
 Receptors not only initiate regulate biochemical events and physiological
function but also are themselves subject to many regulatory and
homeostatic controls.
 These controls include regulation of the synthesis and degradation of the
receptor by multiple mechanisms, covalent modification, association with
other regulatory proteins, and/or relocalization within the cell. Transducer
and effector proteins are regulated similarly.
 Modulating inputs may come from other receptors, directly or indirectly, and
receptors are almost always subject to feedback regulation by their own
signaling outputs.
REGULATION OF RECEPTORS
 Continued stimulation of cells with agonists generally results in a state of
desensitization (also referred to as adaptation, refractoriness, or down-
regulation) such that the effect that follows continued or subsequent
exposure to the same concentration of drug is diminished.
 This is also called as tachyphylaxis
 Eg: Attenuated response to the beta receptor agonist in treatment of
asthma
 Predictably, supersensitivity to agonists also frequently follows chronic
reduction of receptor stimulation.
 Eg: following withdrawal from prolonged receptor blockade (e.g., the long-
term administration of b receptor antagonists such as propranolol )
DRUG RECEPTOR INTERACTION: TERMINOLOGY
 Agonist : An agent which activates a receptor to produce an effect
similar to that of the physiological signal molecule.
 lnverse agonist: An agent which activates a receptor to produce an
effect in the opposite direction to that of the agonist.
 Antagonist: An agent which prevents the action of an agonist on a
receptor or the subsequent response,but doesnot have any effect of its
own.
 Partial agonist: An agent which activates a receptor to produce
submaximal effect but antagonizes the action of a full agonist.
 Ligand (Latin: ligare-to bind): Any molecule which attaches selectively
to particular receptors or sites. The term only indicates affinity or binding
without regard to functional change: agonists and
competitive antagonists are both ligands of the samereceptor.
RECEPTOR OCCUPATION THEORY:
 Clark propounded a theory of drug action based on occupation of receptors
by specific drugs and that the pace of a cellular function can be altered by
interaction of these receptors with drugs which, in fact, are small molecular
ligands.
 He perceived the interaction between the two molecular species,viz.drug
(D ) and receptor (R) to be governed by the law of mass action, and the
effect (E)to be a direct function of the drug-receptor complex (DR) formed:
D + R DR S E
 Subsequently,it has been realized that occupation of the receptor is essential
but not itself sufficient to elicit a response. The agonist must also be able to
activate (induce a conformational change in) the receptor.
 The ability to bind with the receptor designated as Affinity, and the capacity to
induce a functional change in the receptor designated as
intrinsic activity (IA) or efficacy are independent properties.
 Competitive antagonists occupy the receptor but do not activate it. Moreover,
certain drugs are partial agonists which occupy and
submaximally activate the receptor.
 An all or none action is not a must at the receptor. A theoretical
quantity(S) denoting strength of stimulus imparted to the cell was interposed
in the Clark‘s equation
 Depending on the agonist, DR could generate a stronger or weaker S,
probably as a function of the conformational change brought about by the
agonist in the receptor.
 Accordingly: Agonists have both affinity and maximal intrinsic activity (IA
= 1), e.g. adrenaline, histamine, morphine.
 Competitive antagonists have affinity but no intrinsic activity (IA = 0),
e.g.propranolol, atropine, chlorpheniramine, naloxone.
 Partial agonists have affinity and submaximal
intrinsic activity (IA between 0 and 1), e.g. dichloroisoproterenol (on
Badrenergic receptor), pentazocine (on p opioid receptor).
 lnverse agonists have affinity but intrinsic activity with a minus sign
(IAbetween0 and-1), e.g.DMCM (on benzodiazepine receptor)
DISEASES RESULTING FROM RECEPTOR MALFUNCTIONING
 Alteration in receptors and their immediate signaling effectors can be the
cause of disease.
 The loss of a receptor in a highly specialized signaling system may cause a
relatively limited, if dramatic, phenotypic disorder (e.g., deficiency of the
androgen receptor and androgen insensitivity syndrome)
 Deficiencies in widely employed signaling pathways have broad effects, Eg:
as seen in myasthenia gravis and some forms of insulin-resistant diabetes
mellitus, which result from autoimmune depletion of nicotinic cholinergic
receptors or insulin receptors, respectively.
SIGNIFICANCE OF RECEPTOR SUBTYPES
 Molecular cloning has accelerated discovery of novel receptor subtypes,
and their expression as recombinant proteins has facilitated discovery of
subtype-selective drugs.
 When selective ligands are not known, the receptors are more commonly
referred to as isoforms rather than as subtypes. The distinction between
classes and subtypes of receptors, however, often is arbitrary or
historical.
 The a1, a2, and b receptors differ from each other both in ligand
selectivity among drugs and in coupling to G proteins (Gq, Gi, and Gs,
respectively), yet a and b are considered receptor classes and a1 and a2
are considered subtypes. The a1A, a1B, and a1C receptor isoforms differ
little in their biochemical properties, although their tissue distributions are
distinct.
 Pharmacological differences among receptor subtypes are exploited
therapeutically through the development and use of receptor-selective
drugs.
 Such drugs may be used to elicit different responses from a single
tissue when receptor subtypes initiate different intracellular signals, or
they may serve to differentially modulate different cells or tissues that
express one or another receptor subtype.
 Increasing the selectivity of a drug among tissues or among responses
elicited from a single tissue may determine whether the drug’s
therapeutic benefits outweigh its unwanted effects.
THANK YOU
 References:
 Goodman and Gilman’s The Pharmacological basis
of Therapeutics 11th edition
 K.D. Tripathy Essentials of medical Pharmacology
6th edition

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Physiological receptors

  • 1. PHARMACOLOGY OF RECEPTORS: STRUCTURAL AND FUCTIONAL FAMILIES Dr. Santosh M.
  • 2. CONTENTS IN BRIEF  1) Types of receptors  2) Cytoplasmic secondary messengers  3) Regulation of receptors  4) Drug receptor interaction  5) Diseases resulting from receptor malfunctioning  6) Significance of receptor subtypes
  • 3. BRIEF INTRODUCTION  The relatively small number of biochemical mechanisms and structural formats used for cellular signaling is fundamental to the ways in which target cells integrate signals from multiple receptors to produce additive, sequential, synergistic, or mutually inhibitory responses.  The regulatory actions of a receptor may be exerted directly on its cellular target(s), effector protein(s), or may be conveyed by intermediary cellular signaling molecules called transducers.
  • 4. TYPES OF RECEPTORS  1)Receptors as Enzymes: Receptor Protein Kinases and Guanylyl Cyclases:  exert their regulatory effects by phosphorylating diverse effector proteins at the inner face of the plasma membrane.  Most receptors that are protein kinases phosphorylate tyrosine residues in their substrates. Eg: Insulin  are composed of an agonist-binding domain on the extracellular surface of the plasma membrane, a single membrane-spanning element, and a protein kinase domain on the inner membrane face.  For the receptors that bind atrial natriuretic peptides and the peptides guanylin and uroguanylin, the intracellular domain is a guanylyl cyclase that synthesizes the second messenger cyclic guanosine monophosphate (cyclic GMP), which activates a cyclic GMP–dependent protein kinase (PKG) and can modulate the activities of several cyclic nucleotide phosphodiesterases, among other effectors. Eg: ANP, BNP
  • 6. TYPES OF RECEPTORS:  2)Protease Activated Recptor signaling: Proteases that are anchored to the plasma membrane or that are soluble in the extracellular fluid(e.g. thrombin) can cleave ligands or receptors at the surface of cells to either initiate or terminate signal transduction. Eg: ACE inhibitors used for treatment of hypertension  3) Ligand gated ion Channels: These are most important Receptors for several neurotransmitters form agonist-regulated ion- selective channels in the plasma membrane, termed ligand-gated ion channels or receptor operated channels, that convey their signals by altering the cell’s membrane potential or ionic composition.  Eg: Acetyl Choline, Serotonin, GABA etc.
  • 8. TYPES OF RECEPTORS:  4) G Protein Coupled Receptors: G proteins are signal transducers that convey information (i.e., agonist binding) from the receptor to one or more effector proteins. GPCRs include diverse group of biogenic amines, eicosanoids and other lipidsignaling molecules, peptide hormones, opioids, amino acids such as GABA, and many other peptide and protein ligands.  Because of their number and physiological importance, GPCRs are the targets for many drugs; perhaps half of all nonantibiotic prescription drugs are directed toward these receptors that make up the third largest family of genes in humans.  Central to the effect of many GPCRs is release of Ca2+ from intracellular stores.
  • 10. TYPES OF RECEPTORS:  5) Transcription Factors:  Receptors for steroid hormones, thyroid hormone, vitamin D, and the retinoids are soluble DNAbinding proteins that regulate the transcription of specific genes.  Regulatory sites in DNA where agonists bind are receptor-specific: the sequence of a “glucocorticoid-response element,” with only slight variation, is associated with each glucocorticoid-response gene, whereas a “thyroid- response element” confers specificity of the actions of the thyroid hormone nuclear receptor.
  • 11. TYPES OF RECPTORS:  6) Cytoplasmic second messengers:  Binding of an agonist to a receptor provides the first message in receptor signal transduction to effector to affect cell physiology. The first messenger promotes the cellular production or mobilization of a second messenger, which initiates cellular signaling through a specific biochemical pathway.  Eg: cyclic AMP, cyclic GMP, cyclic ADP–ribose, Ca2+, inositol phosphates, diacylglycerol, and nitric oxide (NO).
  • 12. REGULATION OF RECEPTORS  Receptors not only initiate regulate biochemical events and physiological function but also are themselves subject to many regulatory and homeostatic controls.  These controls include regulation of the synthesis and degradation of the receptor by multiple mechanisms, covalent modification, association with other regulatory proteins, and/or relocalization within the cell. Transducer and effector proteins are regulated similarly.  Modulating inputs may come from other receptors, directly or indirectly, and receptors are almost always subject to feedback regulation by their own signaling outputs.
  • 13. REGULATION OF RECEPTORS  Continued stimulation of cells with agonists generally results in a state of desensitization (also referred to as adaptation, refractoriness, or down- regulation) such that the effect that follows continued or subsequent exposure to the same concentration of drug is diminished.  This is also called as tachyphylaxis  Eg: Attenuated response to the beta receptor agonist in treatment of asthma  Predictably, supersensitivity to agonists also frequently follows chronic reduction of receptor stimulation.  Eg: following withdrawal from prolonged receptor blockade (e.g., the long- term administration of b receptor antagonists such as propranolol )
  • 14. DRUG RECEPTOR INTERACTION: TERMINOLOGY  Agonist : An agent which activates a receptor to produce an effect similar to that of the physiological signal molecule.  lnverse agonist: An agent which activates a receptor to produce an effect in the opposite direction to that of the agonist.  Antagonist: An agent which prevents the action of an agonist on a receptor or the subsequent response,but doesnot have any effect of its own.  Partial agonist: An agent which activates a receptor to produce submaximal effect but antagonizes the action of a full agonist.  Ligand (Latin: ligare-to bind): Any molecule which attaches selectively to particular receptors or sites. The term only indicates affinity or binding without regard to functional change: agonists and competitive antagonists are both ligands of the samereceptor.
  • 15. RECEPTOR OCCUPATION THEORY:  Clark propounded a theory of drug action based on occupation of receptors by specific drugs and that the pace of a cellular function can be altered by interaction of these receptors with drugs which, in fact, are small molecular ligands.  He perceived the interaction between the two molecular species,viz.drug (D ) and receptor (R) to be governed by the law of mass action, and the effect (E)to be a direct function of the drug-receptor complex (DR) formed: D + R DR S E
  • 16.  Subsequently,it has been realized that occupation of the receptor is essential but not itself sufficient to elicit a response. The agonist must also be able to activate (induce a conformational change in) the receptor.  The ability to bind with the receptor designated as Affinity, and the capacity to induce a functional change in the receptor designated as intrinsic activity (IA) or efficacy are independent properties.  Competitive antagonists occupy the receptor but do not activate it. Moreover, certain drugs are partial agonists which occupy and submaximally activate the receptor.  An all or none action is not a must at the receptor. A theoretical quantity(S) denoting strength of stimulus imparted to the cell was interposed in the Clark‘s equation
  • 17.  Depending on the agonist, DR could generate a stronger or weaker S, probably as a function of the conformational change brought about by the agonist in the receptor.  Accordingly: Agonists have both affinity and maximal intrinsic activity (IA = 1), e.g. adrenaline, histamine, morphine.  Competitive antagonists have affinity but no intrinsic activity (IA = 0), e.g.propranolol, atropine, chlorpheniramine, naloxone.  Partial agonists have affinity and submaximal intrinsic activity (IA between 0 and 1), e.g. dichloroisoproterenol (on Badrenergic receptor), pentazocine (on p opioid receptor).  lnverse agonists have affinity but intrinsic activity with a minus sign (IAbetween0 and-1), e.g.DMCM (on benzodiazepine receptor)
  • 18. DISEASES RESULTING FROM RECEPTOR MALFUNCTIONING  Alteration in receptors and their immediate signaling effectors can be the cause of disease.  The loss of a receptor in a highly specialized signaling system may cause a relatively limited, if dramatic, phenotypic disorder (e.g., deficiency of the androgen receptor and androgen insensitivity syndrome)  Deficiencies in widely employed signaling pathways have broad effects, Eg: as seen in myasthenia gravis and some forms of insulin-resistant diabetes mellitus, which result from autoimmune depletion of nicotinic cholinergic receptors or insulin receptors, respectively.
  • 19. SIGNIFICANCE OF RECEPTOR SUBTYPES  Molecular cloning has accelerated discovery of novel receptor subtypes, and their expression as recombinant proteins has facilitated discovery of subtype-selective drugs.  When selective ligands are not known, the receptors are more commonly referred to as isoforms rather than as subtypes. The distinction between classes and subtypes of receptors, however, often is arbitrary or historical.  The a1, a2, and b receptors differ from each other both in ligand selectivity among drugs and in coupling to G proteins (Gq, Gi, and Gs, respectively), yet a and b are considered receptor classes and a1 and a2 are considered subtypes. The a1A, a1B, and a1C receptor isoforms differ little in their biochemical properties, although their tissue distributions are distinct.
  • 20.  Pharmacological differences among receptor subtypes are exploited therapeutically through the development and use of receptor-selective drugs.  Such drugs may be used to elicit different responses from a single tissue when receptor subtypes initiate different intracellular signals, or they may serve to differentially modulate different cells or tissues that express one or another receptor subtype.  Increasing the selectivity of a drug among tissues or among responses elicited from a single tissue may determine whether the drug’s therapeutic benefits outweigh its unwanted effects.
  • 21. THANK YOU  References:  Goodman and Gilman’s The Pharmacological basis of Therapeutics 11th edition  K.D. Tripathy Essentials of medical Pharmacology 6th edition