cell signalling , intracellular, extracellular pathway

cell signalling, intracellular, extracellular pathway, GPCR, Ion chanells

1. CELL SIGNALING

» A biological mechanism that occurs in
cells which gives cells an ability to
receive or generate the signals in
response to their surrounding
environment

» Cell to cell communication between
cells is mediated by extracellular signa
molecules. Some of those operate
long distances

2. WHY DO CELLS
COMMUNICATE ?

Maintenance of homeostasis
Control of division and cell death
Adaptation to environmental
conditions

Control of development and growth
Release and production of hormones
and others regulatory molecules
Regulation of metabolism

3. Steps in cell signaling

Signal
removal
and
response
terminatio
n

Changes
due to
receptor-
signal
complex

Synthesis Release Transport
of of of signal binding of
signaling signaling to target signal by
molecule molecule cell specific
receptor

4. Intercellular signaling

- The transfer of information from one cell to
another cell

» Cells signals each other by direct contact
with each other or by the release of a
substance from one cell that is taken up by
another cell

» Important for cells to grow and
normally

5. Types of intercellular
signaling pathways

® Autocrine signaling
© Paracrine signaling
© Endocrine signaling
© Juxtacrine signaling

6. Autocrine signaling

- Autocrine signals target the cell itself.
Sometimes autocrine cells can target
cells close by if they are the same type
of cell as the emitting cell

- An example of this are immune cells

7. » Extracellular
signal

Y Receptor

1 Membrane-attached
signal
Target sites on same cell

Examples: cytokines/immune cells, growth factors

8. Paracrine signaling

» Paracrine signals target cells in the
vicinity of the emitting cell

» Neurotransmitters represent an
example

9. D

Secretory cell Adjacent target cell

Examples: nerve-nerve, nerve-muscle cells, cytokines

12

10. Endocrine signaling

- Endocrine signals target distant cells

» Produce hormones that travel
through the blood to reach all the
parts of the body

11. Blood vessel

1
Hormone secretion le
into blood by endocrine gland Distant target cells

Examples: peptide and steroid hormones

12. Juxtacrine signaling

» Juxtacrine signals target adjacent
(touching)cells

» Transmitted along cell membranes
via protein or lipid components
integral to the membrane

» Capable of affecting either the
emitting cell or cells immedia
adjacent

13. MEMBRANE-ANCHORED
LIGANDS 7

@.g."Notch signalling.

ae

NEIGHBOURING
CELLS

14. Intracellular signaling

- The transmission of molecular signals
from a cell's exterior to its interior

- Transmitted between cells by the
secretion of hormones, which picked up
by different cells

15. ...continued

Dependent on all the cells of its
different organs communicating
effectively with their surroundings

Once a cell picks up a hormonal or
sensory signal, it must transmit this
information from the surface to the
interior parts of the cell

16. EXTRACELLULAR SIGNAL MOLECULE

RECEPTOR PROTEIN

— plasma membrane of
target cell

enzyme protein

altered coll

altered altered gene
metabolism expression

17. Receptors

> Receptors are proteins associated
with cell membranes or located within
the cell

> Receptors “recognize” signalling
molecules by binding to them

> Binding of receptors by signalli
molecules —-> cell behaviour cha

18. Agonist

» An agent which activates a receptor to
produce an effect similar to that of the
physiological signal molecule

19. Inverse agonist

- An agent which activates a receptor to
produce an effect in the opposite
direction to that of the agonist

20. Antagonist

» An agent which prevents the action of
an agonist on a receptor or the
subsequent response, but does not
have any effect of its own

21. Partial agonist

» An agent which activates a receptor to
produce submaximal effect but
antagonizes the action of a full agonist

22. Functions of receptors

» To propagate regulatory signals from
outside to within the effector cell when
the molecular species carrying the
signal cannot itself penetrate the cell
membrane

- To amplify the signal

» To integrate various extracellular and
intracellular regulatory signal

23. Trans
membrane
scaffold

Protein
kinase
receptor
(S/TKR)

Protein
kinase
receptor
(ATK)

G protein
coupled
receptor

Ligand-

channel cadherins)

galedion (e.g., integrins,

Guanylyl
cyclase

as Nuclear

receptor
(Iranscripion
factors)

24. G - protein linked
receptor

Heterotrimeric protein

3 sub - units : alpha, beta , gamma
Alpha binds with GDP and GTP
Beta and gamma anchor to
membrane

25. ...continued

» This group of receptors is the largest
known, and many different signals and
responses can be associated with G —
protein activity

> All have the same structural arrangement
within the membrane - known as a seven
— pass transmembrane protein

» Several hundred types of receptor are
known, which bind signals as diverse as
peptide hormone, amino acids, fatty a
and neurotransmitters

26. ...continued

» Their signaling protein partners are
called G proteins because they bind to
the nucleotide GTP to regulate their
shape and activity

» When activated, they can trigger the
activation of several copies of the same
G protein. Because activated G proteins
dissociate from the GPCR, leaving the
binding site available to bind and
activate, thereby amplifying the effect of
a single signal molecule

27. Families of G- proteins

» Gs subgroup which stimulate
adenylyl cyclase

» Itincludes Gor coupled to olfactory
receptors

» Gi subgroup which inhibit adenylyl
cyclase and activate some Ca?*+ and
K+ channels

28. ...continued

+ Gasubgroup which couple receptors
to calcium mobilisation through
phospholipase Cs that in turn generates
the two second messengers inositol
triphosphate (IPs) and diacylglycerol
(DAG)

» G: subgroup which stimulate
phosphodiesterase following light
stimulation of the retina involving

transducin

29. G proteins and their

physiological effects

| G Protein
be Liver PRET
= Adipose tissue PR glucagon Adenylyleytase Glycogen breakdown
la Kidney le glucagon Adenylyl cyclase Fat breakdown
4 Heart musch ae hormone Ademhlqchse Conservation of water
Ñ Acetslcholine Potassium channel Decreased heart rate
G/G Brai : pumping force
; de Enkephalins, endorphins, Adenyhl eyelase, potassium Changes in neuron €
opioids channels calcium channels activi)
5 Smooth muscle celsin Angiotensin Phospholipase C Muscle contraction,
blood vessels presse ann
u Neurocpithelial cells in Odorant molecules Ademyÿl cyclase Odorant detection
the nose
Iransducin (6) Retinal rod and cone Light cGMP phosphodiesterast Light detection (Y
cells of the eye

30. Messenger

EXTRACELLULAR binding site

FLUID

NOOO

CYTOSOL Segment that
interacts with
G proteins

31. Structure of G-protein
receptors

» The receptor protein forms seven
transmembrane o helices connected
by alternating cytosolic or
extracellular loops

- The N - terminus of the protein is
exposed to the extracellular fluid,
while the C - terminus resides in the
cytosol

32. ...continued

- The extracellular portion of each G
protein - linked receptor has a unique
messenger - binding site, and a
cytosolic loop connecting the fifth and
sixth transmembrane «a helices is
specific for a particular G protein

33. Hosting state
Receptor a

Targot EJ | (Toa | ven
aa

\ Target proteins
GIP hydrolysed \ zung

Me Fal
EA | E
+ a

®

Target
1

39. Kinase receptor

» These are transmembrane proteins
that are composed of at least two
subunits and therefore have a
quaternary structure

» Each of the subunits contains a single
a-helical transmembrane domain, so
they can diffuse relatively easily in the
membrane

40. ...continued

+ The subunits of inactive receptors
dissociate from one another, and only
bind to one another when they come into
contact with the proper ligand

» Their cytoplasmic tails contain protein
kinase domains

- A protein kinase is an enzyme that
attaches phosphate groups to the side
chains of specific amino acids

41. Types of kinase receptor

» Serine/threonine kinase receptor are
more heterogeneous in structure than
tyrosine kinases, and most do not
undergo transautophosphorylation;
instead, they phosphorylate a
separate signaling protein

42. ...continued

» Tyrosine kinase receptor, which
contain two subunits. Each of the two
subunits contains a tyrosine kinase,
and in many cases, each
phosphorylates tyrosines on the
opposite subunit, a behavior called
transautophosphorylation

43. Extracellular

inactive Active

Signal molecule
o”: <> ES

Tyrosine
14) kinase
| domains

44. Tyrosine kinase receptors

» Many receptor tyrosine kinases (RTKs)
trigger a chain of signal transduction
events inside the cell that ultimately
leads to cell growth, proliferation, or the
specialization of cells in a process
known as differentiation

» These processes are tightly controlled ,
so that only specific cells respond when
the appropriate ligand is available

45. ...continued

- Examples of RTKs include the insulin
receptor, the nerve growth factor
receptor and the epidermal growth
factor (EGF)

46. Structure of RTKs

» These receptors often consist of a single
polypeptide chain with only one
transmembrane segment

- The extracellular portion of the receptor
contains the ligand — binding domain

» Inactive receptors are separate
polypeptides with inactive tyrosine
kinase domains

47. ...continued

» Binding to a signaling molecule
causes the two subunits of the
receptor to join together, also called
dimerize

- The resulting phosphotyrosine amino
acids are binding sites for additional
signaling proteins that pass the signal
along the pathway

48. ...continued

» When the cytoplasmic tail of one
subunit is brought close to the
tyrosine kinase domain of the other
subunit, it is phosphorylated on
specific tyrosine amino acids

49. Nuclear receptors

- They are actually located in the
cytoplasm and migrate to the nucleus
after binding with their ligands

> They are composed of a C - terminal
ligand — binding region, a core DNA -
binding domain (DBD) and an N-
terminal domain that contains the AF1
(activation function 1) region

50. ...continued

- The core region has two zinc fingers that
are responsible for recognizing the DNA
sequences specific to this receptor

- The N - terminus interacts with other
cellular transcription factors in a ligand -
independent manner

- Depending on these interactions , it can
modify the binding / activity of the
receptor

51. ...continued

Membrane - permeable signals adhere to
receptor proteins in the cytosol

These receptors typically have very
short signal transduction pathways they
move directly into the nucleus once they
are bound and activated . These are
called nuclear receptors for this reason

52. Steroid
hormone
(cortisol)
O
Plasma =
membrane,

IN

Steroid H
receptor Li

proteins

Nucleus e
Transcription
r—

Steroid response
element

53. Ligand - gated ion
channels

> Itis commonly known as ionotropic
receptors, are a group of
transmembrane ion channel proteins
which open to allow ions such as Nat,
k+, Ca?+ and CI to pass through
membrane in response to the binding
of a chemical messenger such as a
neurotransmitter

54. ...continued

+ When a presynaptic neuron is excited, it
releases neurotransmitter from vesicles
into the synaptic cleft

- The neurotransmitter then binds to
receptors located on the postsynaptic
neuron. If these receptors are ligand -
gated ion channels, a resulting
conformational change opens the ion
channels, which leads to a flow of ions
across the cell membrane

55. ...continued

> This, in turn, results in either a
depolarization, for an excitatory
receptor response, or a
hyperpolarization, for an inhibitory
response

56. Structure of ligand - gated
ion channels

- These proteins are typically composed
of at least two different domains: a
transmembrane domain which
includes the ion pore, and an
extracellular domain which includes
the ligand binding location

57. Acetylcholine Closed Open

signal

Cytosol

59. Reference

© Verma S. P. , Agarwal K.V. , cell biology,

ublished by S. Chand & company Pvt. Ltd. NEW
ELHI, first edition, 2016, page no. 530 - 532

© Rastogi Bala Veer, Aneja R. K. , principles of

biochemistry, published b Scientific
International Pvt. Ltd. NEW DELHI, fifth edition,
page no. 211-219

Plopper George, cell biology, published by jones
& bartlett learning, second edition, 2016, page
no. 372-380
https://www.cancer.gov/publications/dictionaries/
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cellular +signaling+ pathway