Receptor Enzyme

Receptors and Drug Action

A drug is a chemical molecule. When introduced into the
body, it must pass through many barriers, survive alternate
sites of attachment and storage, and avoid significant
metabolic destruction before it reaches the site of action,
usually a receptor on or in a cell.
Action occurs when drug binds to receptor and this
action may be:
• Ion channel is opened or closed
• Second messenger is activated
cAMP, cGMP, Ca++, inositol phosphates, etc.
Initiates a series of chemical reactions
• Normal cellular function is physically inhibited
• Cellular function is “turned on”
 Receptors and Drug Action
⚫ Receptor
Receptor is defined as a macromolecule or binding
site located on the surface or inside the effector
cell that serves to recognize the signal molecule /
drug and initiate the single response to it, but itself
has no other function.
⚫ Functions of receptors are
- Recognition and binding of the ligand.
- Propagation of the message.
- To amplify the signal.
 Receptors and Drug Action
HOW DRUGS ACT

1. Enzyme Inhibition:
Drugs act within the cell by modifying normal biochemical reactions.
Enzyme inhibition may be reversible or non reversible;
competitive or non-competitive.
Antimetabolites may be used which mimic natural metabolites. Gene functions may
be suppressed.

2. Drug-Receptor Interaction:
Drugs act on the cell membrane by physical and/or chemical interactions-
usually through specific drug receptor sites known to be located on the membrane.
Some receptor sites have been identified with specific parts of proteins and nucleic acids.
In most cases, the chemical nature of the receptor site remains obscure.

3. Non-specific Interactions:
Drugs act exclusively by physical means outside of cells. These sites include external
surfaces of skin and gastro-intestinal tract. Drugs also act outside of cell membranes
by chemical interactions. Neutralization of stomach acid by antacids is a good
example
Receptors
 Type of Receptor
⚫ Ion-channel-linked receptors (Ionotropic
receptors)
⚫ G-protein-coupled receptors
(Metabotropic receptors)
⚫ Intracellular receptors
⚫ Receptor enzyme
 Molecular mechanism of receptor /Signal
transduction pathway

The three stages of cell signaling are,

o Reception
o Transduction
o Response
The series of steps involved is
1. Reception of the signal depends on the
receptor protein.
2. The binding signaling molecule activates
the receptor, which in turn activates the
one or more intracellular signaling
pathways.
3. The target is effector proteins, which are
activated when signaling pathway is
activated and implement the appropriate
changes in cell behavior.
 1. Ion channel receptor
1. Ion channel linked receptors are cell membrane bound
receptors are also called ligand-gated ion channels.
2. A ligand-gated ion channel receptor acts as a gate
when the receptor changes shape.
3. When a drug (agonist) molecule binds to an ion
channel and the channel opens, allowing the ions to
move in or out of the cell following their electrical
gradients.
4. The subsequent flow of ions through these channels
can elicit cellular response in the form of
depolarization or hyperpolarization of the cell
membrane.
 Ion channel receptor
⚫ Ex: Nicotinic-cholinergic receptor, GABAA/B
, Glutamate & Glycine receptors.
⚫ Nicotinic cholinergic receptor channel permits
passage of Na+ ions results in depolarisation.
⚫ Benzodiazepines bind the GABA receptor
chloride channel complex and facilitate the
opening of the channel
 Ion channel receptor
Receptors:
•Specific areas of cell membranes (proteins, glycoproteins)*
•When bound to ligand, positive or negative biological responce

L i g a nd

c e l l m e m b r a n e w ith receptor

Biological r e s p o n c e
Signal transduction mechanism
 2. G-protein-coupled receptors
(Metabotropic receptors)
⚫ G protein-coupled receptors (GPCRs) are the largest family of cell-
surface receptors, also known as seven-trans membrane domain
receptors, because they pass through the cell membrane seven
times.
⚫ A GPCR is a plasma membrane receptors which are coupled to the
effector system (enzymes/channels) through GTP binding protein
called as G-protein.
⚫ G-proteins are heterotrimeric, with 3 subunits α, β, γ.
⚫ There are three main varieties of G-protein (Gs, Gi and Gq), among
these Gs and Gi produce stimulation or inhibition of adenyl cyclase
, respectively, while Gq controls phospholipase – C activity.
⚫ Ex: Muscarinic-cholinergic receptor, adrenoceptors,
dopaminergic receptor & 5-HT receptor.
G-Protein coupled receptor
structure
 G protein coupled receptor signal
transduction pathway
⚫ In resting state, GDP is bind to α subunit of α-β-γ trimer.
⚫ When the receptor is activated by the binding of an agonist a
conformational changes occurs results in a high affinity for the α-β
& γ trimer of G-Protein.
⚫ During this process GDP dissociates from α-β-γ subunit while
GTP associates in its place.
⚫ Binding of GTP activates the α-subunit and ultimately dissociates
the remaining β & γ subunits
⚫ The free α-GTP subunit then activates the effector/target cells.
⚫ This is called activation state or switch on state.
G protein coupled receptor signal
transduction pathway
 G protein coupled receptor signal
transduction pathway
⚫ The GTPase of the α-subunit quickly hydrolyses GTP to
GDP and the resultant α-GDP unit then dissociate from
effector and reunite with β-γ unit, complete the cycle.
⚫ Resetting to switch back to the off state.
⚫ Primarily there are three G-protein coupled effector
system through which the G-Protein coupled receptor
works
⚫ a) The Adenylyl cyclase: cAMP system
⚫ b) The Phospholipase-C: Inositol phosphate system
⚫ c) Ion channels
 a) The Adenylyl cyclase: cAMP
effector signal transduction
⚫ All receptors that act via cyclic AMP are coupled to a stimulatory G protein
(Gs), which activates adenylyl cyclase and thereby increases cyclic AMP
concentration.
⚫ Another G protein, called inhibitory G protein (Gi), inhibits adenylyl cyclase,
but it mainly acts by directly regulating ion channels rather than by decreasing
cyclic AMP content.
 b) The Phospholipase-C: Inositol
phosphate signal transduction system

⚫ In this signaling pathway signaling molecule (ligand)

bind to the receptor linked to G-proteins (Gq) and
activate the membrane enzyme phospholipase-C
(PLC).
⚫ Stimulation of PLC leads to the hydrolysis of
Phosphotidyl inositol 4,5 diphosphate (PIP2)
[phospholipid component of plasma membrane]
⚫ On hydrolysis PIP2 splits into two second messengers:
diacylglycerol (DAG) and inositol-1, 4, 5-tri-phosphate
(IP3).
 The Phospholipase-C: Inositol phosphate signal
transduction system
⚫ IP3 being water soluble diffuse through cytoplasm where it trigger the release of
Ca2+ from storage vesicles. The raised concentration of Ca2+ promotes the
binding of Ca2+ to calmodulin which regulate the activity of various enzymes.
⚫ DAG activates a phospholipid and the calcium sensitive protein kinase - C
(PKC) which then phosphorylates specific protein leads to the response.
 c) Ion channel regulation
⚫ G-couple receptors can control the functioning
of ion channel (e.g. K+ and Ca2+ channels) by
the mechanisms that do not involve any role of
secondary messengers.
E.g.:
⚫ In cardiac muscle, muscarinic Ach receptor.
⚫ Opioid analgesics reduce neuronal excitability
by opening K+ channel by this mechanism.
 3.Nuclear receptors (Cytosolic
receptor)
⚫ They are intercellular proteins which are in an inactive
state.
⚫ Binding of agonist activates the receptor.
⚫ The agonist- receptor complex move to the nucleus
where it interacts with DNA, regulate gene
transcription and thereby directs the synthesis of
specific protein to regulate the activity of target cells.
⚫ E.g: Steroidal hormones, thyroid hormones, Vit-D and
retinoids.
Nuclear receptors (Cytosolic
receptor

Drug
Drugs that do not act on receptors: Drugs that do act on receptors:
Acetylcholin
(Neurotransmittor)
Antacida: CaCO3 + HCl ca. 5Å
Acetylcholin Agonists

Diuretica (osmotic) O
Pilocarpine
O
N Carbacholin
Me
O N
Akylating agents (cancer) OH H2N N O
O O N
Cl
H
Cl

Cl Cl Nu Acetylcholin Antagonists
N N
N
Nu
Atropin Cyclopentolat
N
Psoralenes N

OH
OH O
O
O O O
N N
O O N N O
HN R NH2 HN R
O O NH2
N h N Agonist:
O O O O O O
R' R'
Binds to (have affinity for) receptor
Binding leads to biolog. responce
(Agonists have intrinsic activity / efficacy)

Antagonist:
Affinity for receptor
No intrinsic activity
 Receptor
Enzyme
These proteins have a ligand-
binding domain on the
extracellular surface of the
plasma membrane and an
enzyme active site on the
cytosolic side, with the two
domains connected by a
single transmembrane
segment.

Commonly, the receptor enzyme is a protein kinase that phosphorylates Tyr

residues in specific target proteins; the insulin receptor is the prototype for this
group. Other receptor enzymes synthesize the intracellular second messenger
cGMP in response to extracellular signals. The receptor for atrial natriuretic factor
is typical of this type.
Insulin Receptor

The insulin receptor is the

prototype of receptor
enzymes with Tyr kinase
activity. When insulin
binds to its receptor, each
𝛼𝛽 monomer of the
receptor phosphorylates
the 𝛽 chain of its partner,
activating the receptor’s
Tyr kinase activity. The
kinase catalyzes the
phosphorylation of Tyr
residues on other proteins
such as IRS-1.
Receptor Guanylyl Cyclases Generate
the Second Messenger cGMP

Guanylyl cyclases are

another type of receptor
enzyme. When activated, a
guanylyl cyclase produces
guanosine 3,5-cyclic
monophosphate (cyclic GMP,
cGMP) from GTP:
Receptor Guanylyl Cyclases Generate
the Second Messenger cGMP