TARGETS OF DRUG ACTION
PRESENTED BY GROUP B
CONTENTS
Receptors
Targets of drug action
Receptor proteins
Molecular structure of receptors
Type-1 , Type-2 , Type-3 , Type-4
Ion channels as drug receptors
Control of receptor expression
Receptors and associated diseases
Receptors
Proteins located on the cell surface or inside the cell that bind to ligands (e.g.,
hormones, neurotransmitters, growth factors).
Receptors are proteins, which binds to ligands and trigger cellular responses upon
activation and shows responses in immune system
Receptors are involved in chemical signaling between and within cells and helps in
signal transduction pathway
Ion channels
Ion channels are pore-forming membrane proteins whose functions include establishing a
resting membrane potential, shaping action potentials and other electrical signals by
gating the flow of ions across the cell membrane, controlling the flow of ions across
secretory and epithelial cells, and regulating cell volume.
Ion Selectivity
The word ‘selective’ indicates that ions of the ‘correct’ type can permeate through these
channels more easily (i.e. at a faster rate) than the ions of the ‘wrong’ type.
Selective membrane permeability is a key ingredient supporting the concept of
membrane potential: a potential difference (traditionally called the Nernst potential)
appears spontaneously between two ionic solutions of different concentrations separated
by a semipermeable membrane.
The ion channel can be:
Cation selective (Na, K, Ca): It can be selective for each ion or nonselective and
permeable to all three ions.
Anion selective (Cl)
• Voltage-gated ion channels
These channels open when the plasma
membrane is depolarized. They underlie the
mechanism of membrane excitability.
Membrane depolarization is short lived & is
followed by slow process of inactivation.
The examples include selective Sodium,
potassium or calcium channels.
• Ligand-gated ion channels
These are activated by binding of a
chemical ligand to a site on the channel
molecule. Fast neurotransmitters, such
as glutamate, acetylcholine, GABA and
ATP act in this way.
Other examples are:
Ca2+ controlled K+ channels
ATP sensitive K+ channels
G-protein coupled receptors
The are also known as Metabotropic Receptors
or 7-transmembrane-spanning (hepta-
helical) Receptors.
GPCRs make up the largest family and so-named
because the receptor polypeptide chain “snakes”
across the plasma membrane 7 times.
They are membrane receptors that are coupled to
intracellular effector systems via a G-protein.
Receptors for adrenergic amines,
acetylcholine(muscarinic), serotonin, many
peptide hormones and chemokine receptors all
belong to the GPCR family.
Signal Transduction pathway
Binding of agonist to receptors
Coupling of G protein to the receptors
GDP bound to α subunit exchange with GTP
Dissociation of G protein subunits from occupied
receptor;α-GTP also dissociates from βγ subunit
Signal Transduction Mechanism
1. Ligand Binding and Receptors Dimerization:
Ligand binding to the receptor leads to dimerization.
2. Autophosphorylation of Tyrosine Residues:
The association of two intracellular kinase domains allows mutual
autophosphorylation of tyrosine residues to occur.
3. SH2-domain Protein Phosphorylation:
SH2-domain proteins then bind to the phosphorylated receptor and are
themselves phosphorylated.
4. Activation of Downstream Intracellular Signaling Cascade:
Signaling pathways relayed by activated signaling proteins lead to
cellular growth and proliferation.
Targets of G-Proteins
The main targets for G-protein through which GPCRs control different aspects of cell
function.
Adenylyl cyclase: The enzyme responsible for cAMP formation.
Guanylyl cyclase: The enzyme responsible for cGMP formation.
Phospholipase C: The enzyme for IP3 and DAG formation.
Ion channels, particularly calcium and potassium channels.
Rho A/Rho kinase, a system that controls the activity of many signaling pathways
controlling cell growth and proliferation, smooth muscle contraction etc.
Types of G- Mechanism of action Secondary Location
protein coupled messenger
receptors
Gq- coupled Inc. IP3 and DAG cascade cAMP Nerve endings
receptors that causes Inc. calcium Adenylyl cyclase Brain, Eye muscles,
influx and result in Inc. IP3 and DAG neck of bladder ,
muscle contraction prostate , stomach
Gi-coupled Dec. cAMP, Dec. smooth cAMP Hind brain
Receptors muscle contraction Adenylyl cyclase Smooth muscles of
(inhibitory) heart, pancreas,
Gs-coupled Inc. cAMP activates cAMP Lungs, adipose
receptors adenylyl cyclase Adenylyl cyclase tissues, heart smooth
(stimulatory) muscles,
hypothalamus
Enzyme-linked Receptors
Definition:
This is a large and heterogeneous group of membrane receptors responding mainly to protein mediators.
Role in Cellular Regulation:
Regulate cell growth, differentiation, survival, and metabolism
Mediate responses to extracellular signals like hormones, growth factors, and cytokines
Critical for processes like embryogenesis, wound healing, and immune responses
Types of Enzyme – linked
receptors
Receptor Tyrosine Kinase (RTK):
o Contains intrinsic tyrosine kinase activity
o Example: EGFR (Epidermal Growth Factor), VEGFR (Vascular Endothelial Growth Factor), NGFR (Nerve Growth
Factor), PDGFR (Platelet Derived Growth Factor), FGFR (Fibroblast Growth Factor), insulin receptor
Receptor Serine/Threonine Kinase:
o Contains intrinsic serine/threonine kinase activity
o Example: TGF-βR (Transforming Growth Factor)
Receptor Guanylyl Cyclase:
o Contains intrinsic cyclase activity and catalyzes the conversion of GTP to cGMP
o Example: Atrial natriuretic peptide (ANP receptor)
Cytokine Receptors:
o Receptors that associate with proteins that have tyrosine kinase activity and are involved in
immunological responses as well as cell growth and differentiation
o Example: Interferon's and colony-stimulating factors
Receptor Tyrosine Phosphatases:
o Receptors that play a critical role in the removal of phosphate groups from tyrosine residues,
impacting various signaling processes.
Signaling pathway activated by
Enzyme-linked receptors
