SIGNALING MECHANISMS

Dr. Aslam Khan

 CELL SIGNALING MECHANISM

• Communication between cells is called intercellular signaling, and

• Communication within a cell is called intracellular signaling.

 INTERCELLULAR COMMUNICATION
MECHANISMS

• Direct
• cells that are physically connected (Gap junction).
• Contact dependent signaling

• Indirect
• involves chemical diffusion across the interstitial fluid between
cell
• Gap Junction
• Small molecules Ca, amino acid, can move between the cells but not large
like DNA

• Membrane bound ligand based

• both the ligand and the receptor are located on the plasma membrane of the
signaling cell and the target cell

• Autocrine
• Cell releasing the paracrine also has receptors for and responds to
the paracrine it is releasing. E.g. Interleukins; in Immune response,
• Autocrine signaling can promote inappropriate proliferation, as may be the
case in tumor cells.
• Paracrine
• Signals that act locally between cells
that are close together are
called paracrine signals. E.g.
Histamine, gaseous molecule nitric
oxide (NO),

• Synaptic Signaling
• allows the signaling cells (neurons) to
release the chemical ligands,
called neurotransmitters,

• Hormonal/Endocrine Signaling
• reach their targets by traveling in the
blood. Eg sex hormones and cortisol
 STAGES OF CELL SIGNALING:

• Cells receiving signals went through three processes

• Reception
• Transduction
• Response
EXTRACELLULAR CYTOPLASM
FLUID Plasma membrane

1 Reception

Receptor

Signaling
molecule
EXTRACELLULAR CYTOPLASM
FLUID Plasma membrane

1 Reception 2 Transduction

Receptor

Relay molecules in a signal transduction

pathway

Signaling
molecule
EXTRACELLULAR CYTOPLASM
FLUID Plasma membrane

1 Reception 2 Transduction 3 Response

Receptor
Activation
of cellular
response
Relay molecules in a signal transduction
pathway

Signaling
molecule
 TRANSDUCTION:
Cascades of molecular interactions relay signals from
receptors to target molecules in the cell.

• Signal transduction usually involves multiple steps

• Multistep pathways can amplify a signal: A few molecules can
produce a large cellular response
• Multistep pathways provide more opportunities for coordination
and regulation of the cellular response
 Signaling molecule

Receptor
Activated relay
molecule

Inactive
protein kinase
1 Active
protein
kinase
1

Inactive
protein kinase ATP
2 ADP P
Active
protein
PP kinase
Pi 2

Inactive
protein kinase ATP
3 ADP P
Active
protein
PP kinase
Pi 3
Inactive
protein ATP
ADP P
Active Cellular
PP
protein response
Pi
 SMALL MOLECULES AND IONS AS SECOND
MESSENGERS

• The extracellular signal molecule (ligand) that binds to the

receptor is a pathway’s “first messenger”
• Second messengers are small, nonprotein, water-soluble
molecules or ions that spread throughout a cell by diffusion
• Second messengers participate in pathways initiated by G protein-
coupled receptors (GPCR) and Receptor tyrosine kinases (RTKs)
• Cyclic AMP and calcium ions are common second messengers
 CYCLIC AMP

• Cyclic AMP (cAMP) is one of the most widely used

second messengers
• Activate Protein Kinase enzyme

• Adenylyl cyclase, an enzyme in the plasma membrane,

converts ATP to cAMP in response to an extracellular
signal
• Many signal molecules trigger formation of cAMP
• Other components of cAMP pathways are G proteins, G
protein-coupled receptors, and protein kinases
• cAMP usually activates protein kinase A, which
phosphorylates various other proteins

• Further regulation of cell metabolism is provided by G-

protein systems that inhibit adenylyl cyclase
FIGURE 11.12

First messenger
(signaling molecule
such as epinephrine)
Adenylyl
G protein cyclase

G protein-coupled GTP
receptor

ATP
Second
cAMP messenger

Protein
kinase A

Cellular responses
CALCIUM IONS AND INOSITOL TRIPHOSPHATE (IP3)
• Calcium ions (Ca2+) act as a second messenger in many
pathways
• Calcium is an important second messenger because cells
can regulate its concentration
• A signal relayed by a signal transduction pathway may
trigger an increase in calcium in the cytosol
• Pathways leading to the release of calcium involve
Inositol Triphosphate (IP3) and Diacylglycerol (DAG)
as additional second messengers
 EXTRA-
CELLULAR Signaling molecule
FLUID (first messenger)

G protein

DAG
GTP
G protein-coupled PIP2
Phospholipase C
receptor
IP3
(second messenger)

IP3-gated
calcium channel

Endoplasmic Ca2
reticulum (ER)

CYTOSOL
 EXTRA-
CELLULAR Signaling molecule
FLUID (first messenger)

G protein

DAG
GTP
G protein-coupled PIP2
Phospholipase C
receptor
IP3
(second messenger)

IP3-gated
calcium channel

Endoplasmic Ca2
reticulum (ER)
Ca2
(second
CYTOSOL messenger)
 FIGURE 11.14-3

EXTRA-
CELLULAR Signaling molecule
FLUID (first messenger)

G protein

DAG
GTP
G protein-coupled PIP2
Phospholipase C
receptor
IP3
(second messenger)

IP3-gated
calcium channel

Various Cellular
Endoplasmic Ca2 proteins
reticulum (ER) responses
activated
Ca2
(second
CYTOSOL messenger)
 RESPONSE:

CELL SIGNALING LEADS TO REGULATION OF

TRANSCRIPTION OR CYTOPLASMIC ACTIVITIES

• The cell’s response to an extracellular signal is

sometimes called the “output response”
 RECEPTORS AND DRUGS
• In pharmacology, receptors are protein molecules whose
function is to recognize and respond to endogenous
chemical signals. Other macromolecules with which
drugs interact to produce their effects are known as drug
targets
• With some exceptions, drugs act on target proteins,
namely:
• – Receptors
• – Enzymes
• – Carriers
 TYPES OF RECEPTORS
• Two major classes of receptors are recognized based on their
subcellular localization:

• Membrane receptors
• Membrane receptors transduce the signal by modifying intracellular
ion concentrations or generating second messengers or stimulating
formation of biologically active macromolecular complexes

• Intracellular/nuclear receptors.
• These are transcription factors that interact with specific DNA
sequences and change gene expression and therefore cell protein
composition.
TYPES OF RECEPTORS
TYPES OF RECEPTORS
 RECEPTORS IN THE PLASMA MEMBRANE

• Most water-soluble signal molecules bind to specific

sites on receptor proteins that span the plasma
membrane
• There are three main types of membrane receptors
• G protein-coupled receptors
• Receptor tyrosine kinases/Enzyme Linked Receptors
• Ion channel receptors
 G PROTEIN-COUPLED RECEPTORS

• Also called metabotropic receptors or 7-

transmembrane (7-TM, serpentine or heptahelical)
receptors.

• G protein-coupled receptors
(GPCRs) are the largest family of
cell-surface receptors
• A GPCR is a plasma membrane
receptor that works with the help of
a G protein
• G proteins consist of three subunits:
 TYPES OF G PROTEINS
• G(s) Proteins (Gs), catalytic adenylyl
cyclase (AC), phosphodiesterase
(PDE) that hydrolyze cAMP, cAMP-
dependent kinases, with regulatory
(R) and catalytic (C) subunits,
protein substrates (S) of the kinases,
and phosphatases (P’ase), which
remove phosphates from substrate
proteins.
• Open arrows denote regulatory
effects.
TYPES OF G PROTEINS
 TYPES OF G PROTEINS
• G inhibitory Proteins (Gi), inhibit catalytic adenylyl
cyclase (AC),
 TYPES OF G PROTEINS

• Gq ; The Ca2+ -phosphoinositide signaling pathway.

• Key proteins include hormone receptors (R), a G
protein (G), a phosphoinositide-specific
phospholipase C (PLC), protein kinase C substrates of
the kinase (S), calmodulin (CaM), and calmodulin
binding enzymes (E), including kinases,
phosphodiesterases, etc.
• (PIP 2 , phosphatidylinositol-4,5-bisphosphate; DAG,
diacylglycerol; IP 3 , inositol trisphosphate.
• Asterisk denotes activated state.
• Open arrows denote regulatory effects.
• E.g alpha 1 adrenoceptors
 LIGAND-REGULATED TRANSMEMBRANE
ENZYME LINKED RECEPTORS
• The second biggest group after GPCR
• They include four types according to the form of
enzymatic activity of the
• intracellular domain.
• ● Receptor tyrosine kinases (RTKs)
• ● Receptor serine–threonine kinases
• ● Receptor tyrosine phosphatases
• ● Receptor guanylyl cyclases
 LIGAND- AND VOLTAGE-GATED
CHANNELS
• Acetylcholine
• The nicotinic Ach 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 α, 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.
• allows Na + to flow down its concentration
gradient into cells, producing a localized
excitatory postsynaptic potential—a
depolarization.
1 2 3

Gate
closed Ions Gate Gate closed
Signaling open
molecule
(ligand)

Plasma
Ligand-gated
membrane
ion channel receptor Cellular
response
 VOLTAGE-GATED CHANNELS

• Voltage-gated ion channels do not bind neurotransmitters directly but

are controlled by membrane potential; such channels are also
important drug targets.
• Voltage gated Ca, K and Na channels
• Could be excitatory or Inhibitory
 INTRACELLULAR RECEPTORS

• Intracellular receptor proteins are found in the cytosol or nucleus

of target cells
• Small or hydrophobic chemical messengers can readily cross the
membrane and activate receptors
• Examples of hydrophobic messengers are the steroid and thyroid
hormones
• An activated hormone-receptor complex can act as a transcription
factor, turning on specific genes
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein

DNA

NUCLEUS

CYTOPLASM
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

NUCLEUS

CYTOPLASM
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

NUCLEUS

CYTOPLASM
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

mRNA

NUCLEUS

CYTOPLASM
Hormone EXTRACELLULAR
(testosterone) FLUID

Plasma
membrane
Receptor
protein
Hormone-
receptor
complex

DNA

mRNA

NUCLEUS
New protein

CYTOPLASM