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)
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
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
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.
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
22.
23. PKG: Mediator of cGMP Pathway
Protein Kinase G (PKG) — a cGMP-dependent
protein kinase that phosphorylates target proteins
in the cell.
24.
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.
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
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.
In the photoreceptors of the mammalian eye, the presence of light activates phosphodiesterase, which degrades cGMP. The sodium ion channels in photoreceptors are cGMP-gated, so degradation of cGMP causes sodium channels to close, which leads to the hyperpolarization of the photoreceptor's plasma membrane and ultimately to visual information being sent to the brain.