Pharmacodynamics - Receptors 2016 Membrane Receptors

INTERACTION DRUG  BODY
What the drug does to the body
What the body does to the drug

PHARMACODYNAMICS
Receptors
- intracellular receptors
- membrane receptors
- Channel receptors
- G protein-coupled receptors
- Tyrosine-kinase receptors
Drug/receptor interactions
- agonists and antagonists
- potency and efficacy (effectiveness)
- therapeutic index
Drug effects
- therapeutic effects
- side effects
- toxic effects
CELL SURFACE (MEMBRANE) RECEPTORS
Cell-surface (or transmembrane) receptors are membrane-anchored, or

integral proteins that bind to external ligand molecules. This type of
receptor spans the plasma membrane and performs signal transduction,
converting an extracellular signal into an intracellular signal.
This large group of membrane-bound receptors comprises the 7TM or

1TM receptor families. All recruit multiple intracellular signaling cascades
known as “second messengers”.
G PROTEIN-COUPLED RECEPTORS (GPCRs)
The largest and most diverse group of membrane receptors in eukaryotes.
Class A (Rhodopsin-like) most receptors binding monoamines and neurotransmitters

Class B (Secretin receptor family) binding ligands such as secretin, glucagone, calcitonin
Class C (Metabotropic glutamate/pheromone) Ca-sensitive receptors as the mGlu R
Classe D (Fungal mating pheromone receptors)

Classe E (Cyclic AMP receptors)
Classe F (Frizzled/Smoothened)
The largest and most diverse group of membrane receptors in eukaryotes.
They sense molecules outside the cell and activate inside signal transduction
pathways and, ultimately, cellular responses.
GPCRs are also known as seven-transmembrane domain receptors, 7TM receptors

because they pass through the cell membrane seven times.
GPCRs - COMMON STRUCTURE
• The extracellular part of the receptor (N terminal) holds the ligand binding site and
can be glycosylated. These extracellular loops also contain two highly conserved
cysteine residues that form disulfide bonds to stabilize the receptor structure.
• The intracellular parts of the receptor can be phosphorylated. This serves as
additional modulatory mechanism of activity. In addition, lipid anchoring sites allow
for its membrane localization.
• Similar to GPCRs, the adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) also
possess 7 transmembrane domains. However, ADIPOR1 and ADIPOR2 are orientated
oppositely to GPCRs in the membrane (i.e., extracellular C-terminus, cytoplasmic N-
terminus) and do not associate with G proteins.
GPCR ACTIVATION AND SUBSEQUENT EFFECTORS
1) ION CHANNELS 2) ENZYMES

and second messengers
Some GPCRs, when activated, modify Some others amplify the signal
the intracellular ion concentration giving raise to biologically active
second messengers
GPCR and G PROTEINs
• GPCR are so called because they are bound to an intracellular G protein
• Guanine nucleotide-binding proteins (G proteins) act as molecular switches
inside cells, and are involved in transmitting signals from a variety of stimuli.
G PROTEIN
There are two classes of G proteins: the monomeric small GTPases,
and the heterotrimeric G protein complexes.
• The heterotrimeric G protein is

made up of alpha (α), beta (β) and
gamma (γ) subunits.
•The alpha (α) subunit holds the
catalytic GTPase activity.
• The beta (β) and gamma (γ)
subunits can form a stable dimeric
complex referred to as the beta-
gamma complex with regulatory
activity.
Their activity is regulated by factors that control their ability to bind to and
hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP).
ACTIVATION/INACTIVATION CYCLE OF GPCR
ACTIVATION: ligand binding results in G-protein exchange of GTP for GDP. The activated
G-protein then dissociates into an alpha (G-alpha) and a beta-gamma complex.
• G-alpha bound to GTP is

active, and diffuses along
the membrane surface to
activate target proteins,
(often enzymes that
generate second
messengers).
• The beta-gamma
complex is also able to
diffuse and activate
proteins, typically
affecting ion channels
INACTIVATION: it occurs because G-alpha has intrinsic GTPase activity. After GTP
hydrolysis, G-alpha bound to GDP will reassociate with a beta-gamma complex to form
an inactive G-protein that can again associate with a receptor
DISTINCT Gα subunits
The many classes of Gα subunits behave differently in the recognition of the
effector molecule, but share similar activation mechanisms.
•Gi/Go inhibit adenylyl cyclase (AC), activate

K+ channels or inhibit Ca2+ channels
•Gs activates adenylyl cyclase (AC), and
increase intracellular cAMP levels. cAMP
major effect is to bind to and activate cAMP-
dependent kinase (PKA)
•Gq activates phospholipase C

(PLC), which transforms PIP2 into
InsP3 and DAG.
In turn, DAG activates protein C
kinase (PKC) while InsP3
increases intracellular [Ca2+ ].
SOME ENDOGENOUS LIGANDS OF GPCRs

EFFECTOR LIGANDS AND RECEPTOR TYPES
SUBUNIT
s Adenylyl-cyclase (+) noradrenaline (1, 2, 3); dopamine (D1,D5);
Canali al calcio (+) serotonin (5HT4); ACTH, FSH, LH, TFH, GnRH,
GHRH, Vasopressin, Calcitonin, Prostaciclin
i 1,2,3 Adenylyl-cyclase (-) noradrenaline (2); dopamine (D2, D3, D4);
serotonine (5HT1); acetilcholine (M2, M4);
somatostatin (SSTR1-5)
i 3 Potassium channels (GIRK) (+) acetilcholine (M2, M4); dopamine (D2,);
somatostatin (SSTR1,2)
q Phospholipase C (+) noradrenaline (1); serotonine (5HT21); TSH,

TRH, GnRH, LXs, thromboxans
0 1,2 Calcium channels (-) noradrenaline (2); acetilcholine (M2, M4);

somatostatin (SSTR1, 2)
GPCR dimerization
Some GPCR undergo dimerization. This process can be a

homodimerization (M3, 2, GABAB) or a more complex
heterodimerization (D2/SSTR5, AT1/B2, SSTR2/µ opioid).
Constitutive Ligand-induced
δ/κ opioid SSTR5/D2
Adenosin A1/DopamineD1 GABAB/D5
δ opioid/β2 adrenergic
GPCR desensitization mechanisms
GPCRs become desensitized when exposed to their ligand for a prolonged
period of time. There are two recognized forms of desensitization:
1) homologous desensitization, 2) heterologous desensitization,

in which the activated GPCR is wherein the activated GPCR causes
downregulated; downregulation of a different GPCR.
This downregulation is regulated by
protein kinase-dependent
phosphorylation of the intracellular (or
cytoplasmic) receptor domain.
Agonist binding also converts

the receptor into a substrate for
a family of kinases, the G-
protein-coupled receptor
kinases (GRKs). GRKs
phosphorylate only agonist-
activated receptors.
Subsequently, the
phosphorylated receptor
becomes a binding partner for
arrestins.
Arrestins are normally cytosolic proteins, but they recognise agonist-activated,

phosphorylated receptors and bind them. This binding makes the receptor inaccessible for
G-proteins (i.e. the arrestin-bound receptor is desensitised), and it targets the receptor for
internalization. This is because arrestins do not only bind receptors, but they also bind
components of clathrin-coated pits.
Thus, arrestin-bound receptors move into clathrin-coated pits and are then internalized.
This large group of membrane-bound receptors comprises the 7TM or

1TM receptor families. All recruit multiple intracellular signaling cascades
known as “second messengers”.
TYROSINE-KINASE RECEPTORS (RTKs)
RECEPTOR TYROSINE KINASES (RTKS) are the high-affinity cell surface

receptors for many polypeptide growth factors, cytokines, and
hormones. RTKs have been shown not only to be key regulators of
normal cellular processes but also to have a critical role Farmacologia
in the per immagini
Atlante tascabile
development and progression of many types of cancer. II Edizione Italiana
Lullmann
Mohr
TYROSINE-KINASE RECEPTORS (RTKs)
extracel N
transmem
iuxtaglo
catal
intracel C
SCHEMATIC REPRESENTATION OF VARIOUS RTK SUBTYPES AND THEIR

RESPECTIVE COGNATE LIGANDS
RTKs – ACTIVATION MECHANISMS
Ligand binding to the extracellular domain of the TKRs causes dimerization that
results in autophosphorylation and activation of the intracellular kinase domain.
The ensuing phosphorylation of docking sites on the receptor leads to the
recruitment of enzymes, signal transducers and adaptor molecules activating
downstream signalling pathways. The signalling pathways regulate a diverse array
of processes including transcription, translation, metabolism, cell proliferation,
survival, differentiation and motility.
RTKs – TRANSDUCTION SIGNALING CASCADES
(STAT3) - signal transducer and activator of transcription 3
(GRB2) - growth factor receptor-bound protein 2

RAS proteins are small GTPases, which serve as master regulators of a myriad of
signaling cascades involved in highly diverse cellular processes. RAS oncogenes
have been originally discovered as retroviral oncogenes
The RAS/RAF/MEK/ERK pathway is the classical RAS/MAPK signaling pathway

implicated in growth-factor mediated cell proliferation, differentiation and cell
death. RAS activates RAF, which in turn activate mitogen-activated protein kinase
kinase 1/2 (MAP2K1/2 or MEK1/2). MEK1 and MEK2 then phosphorylate their
two known substrates, ERK1 and ERK2

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INTERACTION DRUG  BODY

What the drug does to the body

What the body does to the drug

Cell-surface (or transmembrane) receptors are membrane-anchored, or

This large group of membrane-bound receptors comprises the 7TM or

Class A (Rhodopsin-like) most receptors binding monoamines and neurotransmitters

Classe D (Fungal mating pheromone receptors)

GPCRs are also known as seven-transmembrane domain receptors, 7TM receptors

1) ION CHANNELS 2) ENZYMES

• The heterotrimeric G protein is

• G-alpha bound to GTP is

•Gi/Go inhibit adenylyl cyclase (AC), activate

•Gq activates phospholipase C

q Phospholipase C (+) noradrenaline (1); serotonine (5HT21); TSH,

0 1,2 Calcium channels (-) noradrenaline (2); acetilcholine (M2, M4);

Some GPCR undergo dimerization. This process can be a

1) homologous desensitization, 2) heterologous desensitization,

Agonist binding also converts

Arrestins are normally cytosolic proteins, but they recognise agonist-activated,

This large group of membrane-bound receptors comprises the 7TM or

RECEPTOR TYROSINE KINASES (RTKS) are the high-affinity cell surface

SCHEMATIC REPRESENTATION OF VARIOUS RTK SUBTYPES AND THEIR

(STAT3) - signal transducer and activator of transcription 3

(GRB2) - growth factor receptor-bound protein 2

The RAS/RAF/MEK/ERK pathway is the classical RAS/MAPK signaling pathway

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