Chemical Messengers cAMP and cGMP

Chemical Messengers

1. cAMP and cGMP Second Messengers:

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. cGMP 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

22. PKG: Mediator of cGMP Pathway P rotein K inase G ( PKG ) — a c G MP -dependent protein kinase that phosphorylates target proteins in the cell.

23. Ach Nerve cell endothelial cell NO cGMP Vessel dilation AchR 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 ): Man’s 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.

38. Harmful to Animals?

39. Thank You for Listening! Group 6-B ^_^