Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are intracellular second messengers that mediate the effects of various hormones and neurotransmitters. cAMP mediates processes like steroidogenesis, secretion, ion transport and gene regulation through protein kinase A (PKA)-catalyzed phosphorylation of substrates. cGMP is involved in processes like vision, smooth muscle relaxation and vasodilation through protein kinase G (PKG). Both cAMP and cGMP signals are terminated by phosphodiesterases, which hydrolyze them. Phosphatases also regulate phosphorylation state of substrates.

1. cAMP and cGMP

2. Effects of cAMP
Steroidogenesis
secretion
ion transport
carbohydrate and fat metabolism
enzyme induction
gene regulation
synaptic transmission
cell growth and replication

3. Mediated by:
•Protein phosphorylation-dephosphorylation
serine and threonine residues
-ArgArg/Lys-X-Ser/Thr
-Arg-Lys-X-X-Ser-
Where:
X=any amino acid

4.  Effects of cAMP could be conferred by a specific
protein kinase, by a specific phosphatase, or by
specific substrates for phosphorylation.
 Substrates:
-help define the target tissue
-involve in defining the extent of a particular
response within a given cell
PHOSPHOPROTEINS

5. Mediates the effects of cAMP on gene transcription.
Binds to cAMP responsive element (CRE) in its
nonphosphorylated state and is a weak activator of
transcription.
When phosphorylated by PKA, it binds the coactivator
CREB-binding protein CBP/ p300 and as a result is a
much more potent transcription activator.
Cyclic AMP Response Element Binding
Protein (CREB)

6. Hormonal Regulation of Cellular Processes through
cAMP-dependent protein Kinase (PKA)

7. Terminators of cAMP-Induced
Physiologic Responses
Phosphodiesterases
Phosphatases

8. PHOSPHODIESTERASES
Hydrolyze cAMP to 5′-AMP
rapid turnover of cAMP signal termination of
biologic process after the removal of hormonal stimulus
11 known members

9.  Substrates (cAMP and cGMP)
 hormones
 Intracellular messengers such as
calcium, probably acting through
calmodulin
Subject to regulation by:

10. methylated xanthine derivatives
Ex. Caffeine
-increase intracellular cAMP and mimic
or prolong the actions of hormones
Phosphodiesterase Inhibitors

11. PHOSPHOPROTEIN PHOSPHATASES
Regulated by:
phosphorylation-dephosphorylation
protein-protein interactions

12.  substrate specificity of the phosphoserine-
phosphothreonine phosphatases may be dictated by
distinct regulatory subunits whose binding is
regulated hormonally.
 The best-studied role of regulation by the
dephosphorylation of proteins is that of glycogen
metabolism in muscle

13. Two major types of phosphoserine-
phosphothreonine phosphatases
 Type I - preferentially dephosphorylates the β subunit
of phosphorylase kinase
- regulation of glycogen synthase, phosphorylase, and
phosphorylase kinase
- regulated by phosphorylation of certain of its subunits
 Type II- dephosphorylates the α subunit.

14. Inhibitors
 Two heat-stable protein inhibitors that regulate type I
phosphatase activity
a. Inhibitor-1 is phosphorylated and activated by
cAMP-dependent protein kinases
b. Inhibitor-2, which may be a subunit of the
inactive phosphatase, is also phosphorylated, possibly
by glycogen synthase kinase-3

15. Hormonal Regulation of Cellular Processes through
cAMP-dependent protein Kinase (PKA)

16. is an
INTRACELLULAR
SIGNAL

17. Cyclic GMP (cGMP)
• Derived from the nucleotide GTP using the enzyme
guanylyl cyclase.

18. Function:
• Serves as the second messenger for:
– Atrial natriuretic peptide (ANP)
– Nitric oxide (NO)
– The response of the rods of the retina to light.

19. cGMP Mediated Effects
 Vision (phototransduction)
 smooth muscle relaxation
 Vasodilation
19

20. Other Effects
 Regulates of ion channel conductance
 glycogenolysis
 cellular apoptosis
 secondary messenger in phototransduction
 long-term cellular responses to odor stimulation

21. Guanylyl Cyclase
2 Types:
 Membrane-bound/ Particulate Guanylyl cyclase
-integral proteins of the cell membrane
-activated by peptides
Ex. ANP (atrial natriuretic peptide)
 Soluble/ NO-sensitive Guanylyl cyclase
-located in the cytoplasm
-activated by Nitric Oxide

23. PKG: Mediator of cGMP Pathway
 Protein Kinase G (PKG) — a cGMP-dependent
protein kinase that phosphorylates target proteins
in the cell.

25. Ach
Nerve cell endothelial cell
NO cGMP Vessel dilationAchR
Nitric oxide (NO)
• diatomic gas
• Derived from L-arginine by the enzyme nitric oxide
synthase
• endothelial-derived relaxing factor
• Activates soluble guanylyl cyclase in the cytoplasm
• extremely unstable -> effects are local
ex. signals the dilation of blood vessels.

26. NO mediated cGMP production

27. cGMP in Smooth muscle relaxation
and vasodilation

28. Natriuretic Peptides
• Activate the particulate guanylyl cyclase (pGC).
• Increase in cGMP
• Peptides
• Ex. atrial natriuretic peptide (ANP)
-made of 28 aminoacids.

29. Natriuretic Peptides
• Atrial natriuretic peptide (ANP)
-released from stretched atria (heart
chambers) when blood pressure is elevated
• increase of cGMP by as much as 50-fold

30. Enzymes Involved in cGMP
Pathway
 Nitric Oxide Synthases (NOS): They make nitric
oxide from L-arginine (other substances are also
necessary for this reaction to occur).
 Guanylyl Cyclases (GC; also named guanylate
cyclases and guanyl cyclases): They produce cyclic
GMP.

31.  Cyclic Nucleotide Phosphodiesterases
(PDE): Proteins responsible for the degradation of
cyclic GMP.
 Protein kinases G (PKG): One of the mediators of
cyclic GMP actions in the cell. They modify different
proteins (adding a phosphate) after being activated by
cyclic GMP.
Enzymes Involved in cGMP Pathway

33. cGMP Pathway

34. The cGMP Pathway

35. Degradation
 Phosphodiesterases (PDE)
-hydrolyzing cGMP into 5'-GMP.
-PDE 5, 6 and 9 are cGMP-specific
-while PDE 1, 2, 3, 10 and 11 can hydrolyse both
cAMP and cGMP.

36. cGMP Pathway in phototransduction


37. Phosphodiesterase Inhibitors
 prevent the degradation of cGMP
 thereby enhancing and/or prolonging its effects.

38. Sildenafil (Viagara): Man’s new
Bestfriend

42. Side Effects:

43. Side Effect
 Inhibits PDE6 in retina (albeit with less affinity than
PDE5).
 Result to loss of visual sensitivity but is unlikely to
impair common visual tasks, except under conditions
of reduced visibility when objects are already near
visual threshold.

44. Harmful to Animals?

46. Thank You
for Listening!