Receptors & Signal Transduction
Dr.Tahir
Signal Transduction
• Drugs act as signals, and their receptors act as signal
detectors.
• Receptors transduce their recognition of a bound
agonist by initiating a series of reactions that
ultimately result in a specific intracellular response.
• The magnitude of the response is proportional to the
number of drug–receptor complexes.
• Most receptors are named for the type of agonist that
interacts best with it. For example, the receptor for
histamine is called a histamine receptor.
Families of Receptors
• Pharmacology defines a receptor as any biologic molecule to
which a drug binds and produces a measurable response.
• These receptors may be divided into four families:
– Ligand-gated ion channels,
– G protein–coupled receptors,
– Enzyme-linked receptors,
– Intracellular receptors
The type of receptor a ligand interacts with depends on the
chemical nature of the ligand. Hydrophilic ligands interact with
receptors that are found on the cell surface.
In contrast, hydrophobic ligands enter cells through the lipid bilayers
of the cell membrane to interact with receptors found inside cell.
Ligand-gated ion channels
• The extracellular portion of ligand-gated ion channels usually
contains the ligand binding site………….Binding Domain
• The channel is usually closed until the receptor is activated
(agonist),which opens the channel briefly for a few milliseconds.
• Depending on the ion conducted through these channels, these
receptors mediate diverse functions, (neurotransmission, and
cardiac or muscle contraction).
• For example, stimulation of the nicotinic receptor by acetylcholine
results in sodium influx and potassium outflux, generating an
action potential in a neuron or contraction in skeletal muscle.
• Voltage-gated ion channels may also possess ligand-binding sites
that can regulate channel function. For example, local anesthetics
bind to the voltage-gated sodium channel, inhibiting sodium influx
& decreasing neuronal conduction.
G protein–coupled receptors
• The extracellular domain of this receptor
contains the ligand-binding area, & the
intracellular domain interacts (when
activated) with a G protein or effector
molecule.
• There are many kinds of G proteins
(Gs ,Gi & Gq ).
GPCR
Sometimes, the activated effectors produce second messengers
that further activate other effectors in the cell, causing a signal
cascade effect.
• A common effector, activated by Gs & inhibited by
Gi, is adenylyl cyclase, which produces the second
messenger cyclic adenosine monophosphate
(cAMP).
• Gq activates phospholipase C, generating two other
second messengers: inositol 1,4,5-trisphosphate
(IP3) and diacylglycerol (DAG).
• DAG and cAMP activate different protein kinases
within the cell, leading to a myriad of physiological
effects.
• IP3 regulates intracellular free calcium
concentrations, as well as some protein kinases.
Enzyme-linked receptors
• This family of receptors consists of a protein that may form dimers
or multi subunit complexes. When activated, these receptors
undergo conformational changes resulting in increased cytosolic
enzyme activity, depending on their structure and function.
• This response lasts on the order of minutes to hours.
• The most common enzyme linked receptors (epidermal growth
factor, platelet-derived growth factor, atrial natriuretic peptide,
insulin, and others) possess tyrosine kinase activity as part of their
structure.
• The activated receptor phosphorylates tyrosine residues on itself
and then other specific proteins.
• Phosphorylation can substantially modify the structure of the target
protein, thereby acting as a molecular switch e.g., Insulin receptor.
Intracellular receptors
• The fourth family of receptors differs considerably from the other
three in that the receptor is entirely intracellular, & therefore,
the ligand must diffuse into the cell to interact with the receptor.
• The primary targets of these ligand–receptor complexes are
transcription factors in the cell nucleus.
• Binding of the ligand with its receptor generally activates the
receptor via dissociation from a variety of binding proteins.
• This activated complex then regulates gene expression.
• This leads to transcription of DNA into RNA and translation of
RNA into an array of proteins.
• The time course of activation and response of these receptors is
on the order of hours to days. For example, steroid hormones
exert their action on target cells via intracellular receptors.
• Other targets of intracellular ligands are
structural proteins, enzymes, RNA, &
ribosomes. For example, tubulin is the target
of antineoplastic agents such as paclitaxel the
enzyme dihydrofolate reductase is the target
of antimicrobials such as trimethoprim & the
50 S subunit of the bacterial ribosome is the
target of macrolide antibiotics such as
erythromycin.
