This document summarizes the cyclic AMP (cAMP) signaling pathway. It describes how extracellular signaling molecules called first messengers bind to G protein-coupled receptors, activating G proteins that stimulate the enzyme adenylyl cyclase to produce the second messenger cAMP. cAMP then activates the protein kinase A pathway and triggers cellular responses. Negative feedback mechanisms like phosphorylation and recruitment of arrestins terminate the signal by desensitizing the receptor. The cAMP pathway is an important intracellular signaling system that relays signals from surface receptors to drive changes in cell metabolism, proliferation, and other functions.

1. Cyclic AMP Pathway
Second Messenger
Continuation of Cell Communication
ARIANE RUBY B. SOGO-AN

2. Objectives :
• Explain the role of the Primary and Secondary
Messengers in the cAMP Pathway
• Determine the steps during the cAMP
pathway.

3. Communication
• How important is communication in our
everyday life?
– Achieving productivity
– Maintaining strong relationships
– Understand each other
– Make the proper response

4. Cell Communication/Signalling
• Critical for the function and survival of cells
that compose a multicellular animal.
– Ways/modes:
• Adjacent Cells – Gap junctions
• Specific contact between cells – Specific molecules on
cell surface
• Through intercellular chemical messengers

6. Second Messengers
• Second messengers are intracellular signalling
molecules released by the cell to trigger
physiological changes such
as proliferation, differentiation, migration,
survival, and apoptosis.
• Secondary messengers are therefore one of
the initiating components of
intracellular signal transduction cascades.

7. INTRODUCTION
• Second messengers are molecules that relay
signals from receptors on the cell surface in
accordance to the type of first messenger to
produce biochemical signal to target
molecules inside the cell.
• They greatly amplify the strength of the signal,
cause some kind of change in the activity of
the cell.
• They are a component of cell signaling
pathways.

8. Second messengers
• Short lived intracellular signaling molecules
• Elevated concentration of second messenger
leads to rapid alteration in the activity of one
or more cellular enzymes
• Removal or degradation of second messenger
terminate the cellular response

9. • The cell releases second messenger molecules
in response to exposure to extracellular
signals - the First messengers.
• Because hormones and neurotransmitters
typically comprise biochemically hydrophilic
molecules, first messengers may not
physically cross the phospholipid bilayer cell
membrane to initiate changes within the cell
directly.

10. • This functional limitation necessitates the cell
to devise signal transduction mechanisms to
transduce first into second messengers, so
that the extracellular signal may be
propagated intracellularly.
• An important feature of the second
messenger signaling system is that second
messengers may be coupled downstream to
multi-cyclic kinase cascades to greatly amplify
the strength of the original first messenger
signal.

11. Signalling sequence in the Target Cell
• Reception
– Binding of a signal molecule with a specific
receptor of the target cells.
• Transduction
– Process of changing the signal into the form
necessary to cause the cellular response. May or
may not include cascade of reaction that includes
several different molecules.

12. Signalling sequence in the Target Cell
• Response
– Transduced signal causes a specific cellular
response.

13. Steps in Communication Via
Extracellular signals
1. Synthesis
2. Release of the signalling molecule by the
signalling cell
3. Transport of the signal to the target cell
4. Binding of the signal by a specific receptor
protein leading to its activation
5. Initiation of one or more intracellular signal
transduction pathways by the acticvated
receptor

14. 6. Specific changes in the cellular function,
metabolism and development
7. Removal of the signal

15. Cell Communication/Signalling
• Cell communication systems based on surface
receptors have three (3) components:
– The extracellular signal molecules released by
controlling cells
– The surface receptors on target cells that recieves
the signals
– The internal response pathways triggered when
the receptors binds a signal.

16. Intercellular chemical messengers
• One cell “Controlling Cell” synthesizes specific
molecule that acts a signaling molecule to affect
the activity of another cell called the target cell.
• Example:
– In response to stress, cells of mammal’s adrenal
gland secrets hormones ephinephrine into the
bloodstream. Epinephrine acts on target cells to
increase the amount of glucose in the blood.

17. Ligand Binding to it complementary cell Receptor
The signaling molecule acts as a ligand, which binds to a structurally
complementary site on the extracellular or membrane-spanning
domains of the receptor.

19. Overview of seven major classes of cellsurface receptors

20. GASES
NO
H2S
CO
HYDROPHOBIC
Diacylglycerol
Phosphatidylinositols
HYDROPHILIC
cAMP
cGMP
IP3
Ca2+.
TYPES OF SECOND MESSENGERS

21. • The binding of ligands (“first messengers”) to
many cellsurface receptors leads to a short-
lived increase (or decrease) in the
concentration of certain low-molecular-weight
intracellular signaling molecules termed
second messengers.
• Other important second messengers are Ca2
and various inositol phospholipids, also called
phosphoinositides, which are embedded in
cellular membranes.

22. Four common intracellular second messengers.

23. More receptors using the same second messenger system

24. Reception
The G Protein Coupled Receptor

25. ALL (GPCRs) contain seven membrane-spanning regions with their N-terminal
segment on the exoplasmic face and their C-terminal segment on the cytosolic face
of the plasma membrane
Schematic diagram of the general structure of G protein–coupled receptors.

29. • The signal-transducing G
proteins contain three
subunits designated , , and .
During intracellular signaling
the and subunits remain
bound together and are
usually referred to as the G
subunit.
• The G subunit is a GTPase
switch protein that
alternates between an active
(on) state with bound GTP
and an inactive (off) state
with bound GDP

30. The ability of a G protein to interact with other proteins and thus transduce a signal differs
in the GTP-bound “on” state and GDP-bound “off” state.

31. • These guanine nucleotide–binding proteins
are turned “on” when bound to GTP and
turned “off” when bound to GDP. Signal-
induced conversion of the inactive to active
state is mediated by a guanine nucleotide–
exchange factor (GEF), which causes release
of GDP from the switch protein.

32. • Subsequent binding of GTP, favored by its high
intracellular concentration, induces a
conformational change in two segments of the
protein, termed switch I and switch II, allowing
the protein to bind to and activate other
downstream signaling proteins.
• The intrinsic GTPase activity of the switch
proteins then hydrolyzes the bound GTP to GDP
and Pi, thus changing the conformation of switch
I and switch II from the active form back to the
inactive form. The rate of GTP hydrolysis
frequently is enhanced by a GTPase-accelerating
protein (GAP)

33. Hormone-induced activation and inhibition of adenylyl cyclase in adipose cells.

35. Conversion of ATP to cAMP

36. Protein Kinase A

37. Synthesis and degradation of glycogen.

38. Regulation of glycogen metabolism by cAMP in liver and muscle cells.

39. Mechanisms Regulate Signaling
from G Protein–Coupled Receptors
• 1. The affinity of the receptor for hormone
decreases when the GDP bound to Gs is replaced
with a GTP following hormone binding.
• 2. The GTP bound to Gs is quickly hydrolyzed,
reversing the activation of adenylyl cyclase and
production of cAMP.
• 3. cAMP phosphodiesterase acts to hydrolyze
cAMP to 5-AMP, terminating the cellular
response.

40. • The intracellular levels of cAMP are regulated
by the balance between the activities of two
enzymes: adenylyl cyclase (AC) and cyclic
nucleotide phosphodiesterase (PDE).

41. • When a Gs protein–coupled receptor is exposed
to hormonal stimulation for several hours, several
serine and threonine residues in the cytosolic
domain of the receptor become phosphorylated
by protein kinase A (PKA).
• The phosphorylated receptor can bind its ligand,
but ligand binding leads to reduced activation of
adenylyl cyclase; thus the receptor is
desensitized.
• This is an example of feedback suppression, in
which the end product of a pathway (here
activated PKA) blocks an early step in the
pathway (here, receptor activation).

42. Role of -arrestin in GPCR desensitization and signal transduction.

44. END OF REPORT