23-May-18

Pharm-
3505

Pharmacology II

Cellular communication

Cellular communication is a term used to identify different types of

communication methods between living cells. Some of the methods
include cell signalling among others.
This process allows millions of cells to communicate and work together to
perform important bodily processes that are necessary for survival.

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Stages of cell communication/ signaling

1. Reception: A cell detects a signaling molecule from the outside of the cell. A signal is
detected when the ligand binds to a receptor protein on the surface of the cell or inside
the cell. These trans-membrane receptors are able to transmit information from
outside the cell to the inside because they change conformation when a specific ligand
binds to it.
2. Transduction: When the signaling molecule binds to the receptor, it changes the
receptor protein. This change initiates the process of transduction. Usually,
transduction requires a series of changes in a sequence of different molecules (called a
signal transduction pathway) but sometimes can occur in a single step. Each relay
molecule in the signal transduction pathway changes the next molecule in the pathway.
3. Response: Finally, the signal triggers a specific cellular response. At the end, the end of
a signal pathway leads to the regulation of a cellular activity.

Stages of cell communication

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General principles of signaling by cell-surface

receptors
Communication by extracellular signals usually involves:
1. synthesis of the signaling molecule by the signaling cell
and its incorporation into small intracellular vesicles,
2. its release into the extracellular space by exocytosis,
3. and transport of the signal to the target cell
4. where the signaling molecule binds to a specific cell-
surface receptor protein leading to activation of the
receptor.
5. the activated receptor then initiates one or more
intracellular signal-transduction pathways
6. (a) leading to specific changes, usually short-term, in
cellular function, metabolism. or movement (b) or to
long-term changes in gene expression or development
7. Termination of the cellular response is caused by
intracellular signaling molecules that inhibit receptor
function
8. and by removal of the extracellular signal

Lodish et al, Molecular Cell Biology p624 6e

Signal transduction
Transduction
 Signal transduction is the process by which a chemical or physical signal is transmitted
through a cell as a series of molecular events, most commonly protein phosphoryla-
tion catalyzed by protein kinases, which ultimately results in a cellular response.
 Cascade of molecular interactions relay signals from receptors to target molecules in
the cell.
 Signal transduction usually involves multiple steps

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Representation of signal transduction pathway

Signal transduction is the combination of following phenomenon:
1. Signal reception
2. Integration
3. Amplification
4. A target that is affected
5. Termination

 Thus signal transduction begins with receiving signal to the cell receptor and end with a
change in cellular function.
 The cell receptor can be of various types: G-protein coupled receptor, tyrosin kinase
receptor etc. The transduction process is typically mediated via a cascade of some
important second messengers including cAMP, cGMP, calcium ion, inositol 1, 4, 5-
trisphosphate, (IP 3), and diacylglycerol (DAG).
 Second messengers are intracellular molecules that change in concentration in response
to environmental signals and involve in conveying information inside the cell.

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Common second messengers

Signal amplification pathways

 The phenomenon in which when
receptor proteins interact with the
signal molecules at the surface of the
cell, in most cases signals are relayed
to the cytoplasm or the nucleus by
second messengers which influences
the activity of one or more enzymes or
genes inside the cell.

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 Most enzymes linked and G-protein

linked receptor use a chain of other
protein messenger to amplify the signal
as it is being relayed
 Thus in case of protein kinase one cell
surface receptor activates many G
protein molecules.
 Each G protein activates many adenylyl
cyclases. Each cyclic AMP in turn will
activate protein kinase which then
activates several molecules of a specific
enzyme.

Signaling mechanisms & drug action

We should also consider different structural families of receptor protein and this allows us
to ask basic questions with important clinical implications:
 Why do some drugs produce effects that persist for minutes, hours, or even days after
the drug is no longer present?
 Why do responses to other drugs diminish rapidly with prolonged or repeated
administration?
 How do cellular mechanisms for amplifying external chemical
 signals explain the phenomenon of spare receptors?
 Why do chemically similar drugs often exhibit extraordinary selectivity in their actions?
 Do these mechanisms provide targets for developing new drugs?

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 Most transmembrane signaling is accomplished by a small number of different

molecular mechanisms.
 Each type of mechanism has been adapted, through the evolution of distinctive protein
families, to transduce many different signals.
 These protein families include receptors on the cell surface and within the cell, as well
as enzymes and other components that generate, amplify, coordinate, and terminate
postreceptor signaling by chemical second messengers in the cytoplasm.
 Five basic mechanisms of transmembrane signaling are well understood (see figure).
 Each represents a different family of receptor protein and uses a different strategy to
circumvent the barrier posed by the lipid bilayer of the plasma membrane.

Katzung p26 e14

Basic mechanisms of transmembrane signaling

1. A lipid-soluble ligand that crosses the membrane and acts on an intracellular receptor.
2. A transmembrane receptor protein whose intracellular (enzymatic) activity is allosterically
regulated by a ligand that binds to a site on the protein’s extracellular domain.
3. A transmembrane receptor that binds and stimulates an intracellular protein tyrosine
kinase.
4. A ligand-gated transmembrane ion channel that can be induced to open or close by the
binding of a ligand; or
5. A transmembrane receptor protein that stimulates a GTP-binding signal transducer
protein (G protein), which in turn modulates production of an intracellular second
messenger.
Although the five established mechanisms do not account for all the chemical signals
conveyed across cell membranes, they do transduce many of the most important signals
exploited in pharmacotherapy.

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Transmembrane signaling mechanism

(A, C, substrates; B, D, products; R, receptor; G, G protein;

Katzung Pharmacology p26 E, effector [enzyme or ion channel]; Y, tyrosine; P, phosphate.)

Intracellular Receptors for Lipid-Soluble Agents

 Several biologic ligands are sufficiently lipid-soluble to cross the plasma membrane and
act on intracellular receptors. One class of such ligands includes steroids
(corticosteroids, sex steroids, vitamin D), and thyroid hormone, whose receptors
stimulate the transcription of genes by binding to specific DNA sequences (often called
response elements) near the gene whose expression is to be regulated.

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Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine

Kinases
 This class of receptor molecules
mediates the first steps in signaling by
insulin, epidermal growth factor (EGF),
platelet-derived growth factor (PDGF),
atrial natriuretic peptide (ANP),
transforming growth factor-β (TGF-β),
and many other trophic hormones.
 These receptors are polypeptides
consisting of an extracellular hormone-
binding domain and a cytoplasmic
enzyme domain, which may be a
protein tyrosine kinase, a serine kinase,
or a guanylyl cyclase

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 Mechanism of activation of the

epidermal growth factor (EGF) receptor, a
representative receptor tyrosine kinase.
The receptor polypeptide has
extracellular and cytoplasmic domains,
depicted above and below the plasma
membrane. Upon binding of EGF (circle),
the receptor converts from its inactive
monomeric state (left) to an active
dimeric state (right), in which two
receptor polypeptides bind
noncovalently. The cytoplasmic domains
become phosphorylated (P) on specific
tyrosine residues (Y), and their enzymatic
activities are activated, catalyzing
phosphorylation of substrate proteins (S).

Ligand- and Voltage-Gated Channels

 Many of the most useful drugs in clinical medicine act by mimicking or blocking the
actions of endogenous ligands that regulate the flow of ions through plasma membrane
channels. The natural ligands of such receptors include acetylcholine, serotonin, GABA,
and glutamate. All of these agents are synaptic transmitters.
 For example, acetylcholine causes the opening of the ion channel in the nicotinic
acetylcholine receptor (nAChR), which allows Na+ to flow down its concentration
gradient into cells, producing a localized excitatory postsynaptic potential—a
depolarization

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 The nicotinic acetylcholine (ACh) receptor, a ligand

gated ion channel. The receptor molecule is
depicted as embedded in a rectangular piece of
plasma membrane, with extracellular fluid above
and cytoplasm below. Composed of five subunits
(two a, one β, one γ, and one δ), the receptor
opens a central transmembrane ion
channel when ACh binds to sites on the
extracellular domain of its α subunits.

 Cytokine receptors, like receptor

tyrosine kinases, have extracellular
and intracellular domains and form
dimers. However, after activation
by an appropriate ligand, separate
mobile protein tyrosine kinase
molecules (JAK) are activated,
resulting in phosphorylation of
signal transducers and activation of
transcription (STAT) molecules.
STAT dimers then travel to the
nucleus, where they regulate
transcription.

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G Proteins & Second Messengers

 Many extracellular ligands act by increasing the intracellular concentrations of second messengers
such as cyclic adenosine-3’,5’- monophosphate (cAMP), calcium ion, or the phosphoinositides.
 In most cases, they use a transmembrane signaling system with three separate components.
 First, the extracellular ligand is selectively detected by a cell-surface receptor. The receptor in turn
triggers the activation of a GTP-binding protein (G protein) located on the cytoplasmic face of the
plasma membrane.
 The activated G protein then changes the activity of an effector element, usually an enzyme or ion
channel. This element then changes the concentration of the intracellular second messenger.
 E.g, cAMP, the effector enzyme is adenylyl cyclase, a membrane protein that converts intracellular
adenosine triphosphate (ATP) to cAMP.
 The corresponding G protein, Gs, stimulates adenylyl cyclase after being activated by hormones and
neurotransmitters that act via specific Gs-coupled receptors. There are many examples of such
receptors, including β adrenoceptors, glucagon receptors, thyrotropin receptors, and certain
subtypes of dopamine and serotonin receptors

G proteins and their receptors and effectors

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