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
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 subunit
of phosphorylase kinase - regulation of glycogen synthase,
phosphorylase, and phosphorylase kinase - regulated by
phosphorylation of certain of its subunits Type II-
dephosphorylates the 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.
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. PKG: Mediator of cGMP Pathway Protein Kinase G (PKG) a
cGMP-dependent protein kinase that phosphorylates target proteins
in the cell.
23. 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.
24. NO mediated cGMP production
25. cGMP in Smooth muscle relaxation and vasodilation
26. Natriuretic Peptides Activate the particulate guanylyl
cyclase (pGC). Increase in cGMP Peptides Ex. atrial natriuretic
peptide (ANP) -made of 28 aminoacids.
27. 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
28. 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.
29. 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
30. cGMP Pathway
31. The cGMP Pathway
32. 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.
33. cGMP Pathway in phototransduction
34. Phosphodiesterase Inhibitors prevent the degradation of
cGMP thereby enhancing and/or prolonging its effects.
35. Sildenafil (Viagara): Mans new Bestfriend
36. Side Effects:
37. 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.