cAMP, Pathway

1. Second Messenger:
Cyclic AMP Pathway
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. What do you think these people are doing in this picture?

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

5. 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

8. The Hormone System
Hormones are secreted by glands into the blood stream.
There are two kinds of glands:
Exocrine glands secrete chemicals to the outside, or to
body cavities, usually through ducts (tubes). E.g. sweat
glands, mammary glands, digestive glands.
Endocrine glands do not have ducts but secrete chemicals
directly into the tissue fluid whence they diffuse into the
blood stream. E.g. thyroid gland, pituitary gland, adrenal
gland. The hormone-secreting glands are all endocrine
glands.

10. • Once a hormone has diffused into the
blood stream it is carried all round the
body to all organs. However, it only affects
certain target organs, which can respond
to it.
• These target organs have specific receptor
molecules in their cells to which the
hormone binds. These receptors are
protein molecules, and they form
specific hormone-receptor complexes,
very much like enzyme-substrate
complexes. Cells without the specific
receptor will just ignore a hormone.
• The hormone-receptor complex can affect
almost any aspect of a cell’s function,
including metabolism, transport, protein
synthesis, cell division or cell death.

12. 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.

13. • 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.

14. 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

15. • 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.

16. • 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.

17. • 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.

18. 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.

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

20. 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

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

22. 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.

23. 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.

24. • The specificity of a receptor refers to its ability
to distinguish closely related substances. The
insulin receptor, for example, binds insulin and
a related hormone called insulin-like growth
factor 1, but no other peptide hormones.

25. 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.

27. • Addition of two methyl groups to epinephrine
generates isoproterenol, an agonist that binds
to epinephrine receptors on bronchial smooth
muscle cells about tenfold more strongly than
does epinephrine.
• The antagonist alprenolol and related
compounds, referred to as beta-blockers, have
a very high affinity for these epinephrine
receptors. Such antagonists are used to slow
heart contractions in the treatment of cardiac
arrhythmias and angina.

28. Overview of seven major classes of cellsurface receptors

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

30. • 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.

31. Four common intracellular second messengers.

32. More receptors using the same second messenger system
cGMP – Atrial Natreuretic Factor – Guanylate Cyclase
Dicylglycerol – Insulin, Thyroid stimulating hormone
IP3- Leutenizing Hormone, Parathyroid Hormone,
Thyrotropin releasing hormone

33. • In liver cells, for instance, the hormones
epinephrine, glucagon, and ACTH bind to
different members of the G protein–coupled
receptor family, bureceptors activate the same
signal-transduction pathway, one that
promotes synthesis of cyclic AMP (cAMP).

34. ITS VIDEO TIME!!!!

35. The G Protein Coupled Receptor
The G Protein Coupled Receptor

36. The G Protein Coupled Receptor
• The human genome, for instance, encodes
several thousand G protein–coupled
receptors.
• These include receptors in the visual, olfactory
(smell), and gustatory (taste) systems, many
neurotransmitter receptors, and most of the
receptors for hormones that control
carbohydrate, amino acid, and fat metabolism.

37. 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.

38. • All receptors of this type have the same
orientation in the membrane and contain
seven transmembrane -helical regions (H1–
H7), four extracellular segments (E1–E4), and
four cytosolic segments (C1–C4). The carboxyl-
terminal segment (C4), the C3 loop, and, in
some receptors, also the C2 loop are involved
in interactions with a coupled trimeric G
protein.

42. • 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

43. Ligand Binding Specificity
• The response of a cell or tissue to specific
external signals is dictated by the particular
receptors it possesses, by the signal-transduction
pathways they activate, and by the intracellular
processes ultimately affected.
• Each receptor protein is characterized by binding
specificity for a particular ligand, and the
resulting receptor-ligand complex exhibits
effector specificity

44. 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.

45. • 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.
• All G proteins contain regions like switch I and
switch II that modulate the activity of specific
effector proteins by direct protein-protein
interactions when the
G protein is bound to GTP.

46. • 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)

47. Application
• Some bacterial toxins contain a subunit that
penetrates the plasma membrane of cells and
catalyzes a chemical modification of Gs·GTP
that prevents hydrolysis of bound GTP to GDP.
As a result, Gs remains in the active state,
continuously activating adenylyl cyclase in the
absence of hormonal stimulation.

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

50. Conversion of ATP to cAMP

51. Protein Kinase A

52. Synthesis and degradation of glycogen.

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

54. 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.

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

56. • 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).

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

59. END OF REPORT