EC Emergency Medicine and Critical Care

Every activity a cell is involved with is regulated by signals originating at the surface of the cell. Chemical substances that convert these extracellular signals received by cell surface receptors to intracellular signals are called second messenger molecules (second messengers). Activation by diffusible second messenger molecules and activation by recruitment of proteins to the plasma membrane constitute two major mechanisms of signal transduction pathways of a cell. Intracellular protein kinases or intracellular ligand-gated channels are activated by second messengers. The degradation of these second messengers results in signal termination. Protein kinase A (PKA) and protein kinase G (PKG) are involved in numerous human biological cellular processes. Cyclic nucleotides namely cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are among the second messengers. A number of human diseases are associated with cyclic nucleotide signal pathways some of which are Alzheimer’s disease, asthma, topic dermatitis, attention deficit hyperactivity disorders, bipolar disorders, chronic obstructive pulmonary diseases, cirrhosis of the liver, Cushing’s syndrome, diabetic diseases albinism, Barrter’s disease, cancer, Down’s syndrome, erythermalgia, Fanconi anaemia, glaucoma, Huntington’s disease, infertility etc. Numerous chemical substances such as cyclic nucleotide activators and/or inhibitors, protein kinases activators and/or inhibitors, phosphodiesterases inhibitors have been used as therapeutic agents against these diseases arising from defects in the signal pathways of the cyclic nucleotides.

Keywords: Cyclic Nucleotides Signaling Pathways; Human Diseases; Therapeutic Agents

1. Mhaske A and Tauro S. “Overview of cell signaling and cell communication”. Journal Pharmaceutical Biology2 (2015): 104-107.
2. Gawad JK., et al. “Immunobiology (6th Edition.)”., In: Janeway C, Travers P, Walport M, Shlomchik M (Editions.)., Churchill Livingstone, UK (2004): 203-224.
3. Oppermann M. “Chemokine receptor CCR5: insights into structure, function, and regulation”. Cellular Signaling11 (2004): 1201-1210.
4. Heldin CH., et al. “Signals and receptors”. Cold Spring Harbor Perspectives in Biology 4 (2016): a005900.
5. Amol P., et al. “Cyclic adenosine monophosphate: Recent and future perspectives on various diseases”. Journal Applied Pharmaceutical Science3 (2022): 1-15.
6. Kotob SE. “An overview of cellular signal transduction pathway”. Biomedical Journal Science and Technical Research2 (2021): 230213-30229.
7. Fimia GM and Sassone-Corsi P. “Cyclic AMP signaling”. Journal Cell SciencePt 11 (2001): 1971-1972.
8. Ab Naafs M. “Second messengers in endocrinology: a mini-review of the cyclic nucleotides”. Endocrinol Metabolism International Journal6 (2017): 347-350.
9. Beavo JA and Brunton LL. “Cyclic nucleotide research -- still expanding after half a century”. Nature Review Molecular Cell Biology9 (2002): 710-718.
10. Liscovitch M and Cantley LC. “Lipid second messengers”. Cell3 (1994): 329-334.
11. Thatcher JD. “The inositol trisphosphate (IP3) signal transduction pathway”. Science Signal119 (2010).
12. Newton AC., et al. “Second messengers”. Cold Spring Harbor Perspectives in Biology 8 (2016): a005926.
13. Krauss G. “Biochemistry of Signal Transduction and Regulation”. In: Krauss G (Edition.)., Wiley Publishers, USA (2015): 15.
14. Lomas O and Zaccolo M. “Phosphodiesterases maintain signaling fidelity via compartmentalization of cyclic nucleotides”. Physiology 29 (2014): 141-149.
15. Pifferi S., et al. “Cyclic nucleotide-gated ion channels on sensory transduction”. FEBS Letters 580 (2006): 2853-2859.
16. Shabb JB. “Physiological substrates of cAMP-dependent protein kinase”. Chemical Review 101 (2001): 2381-2411.
17. Larsson HP. “How is the heart rate regulated in the sinoatrial node?. Another piece to the puzzle”. Journal General Physiology 36 (2010): 237-241.
18. Gopalakrishnan L and Scarpulla RC. “Differential regulation of respiratory chain subunits by a CREB-dependent signal transduction pathway. Role of cyclic AMP in cytochrome c and Coxiv gene expression”. Journal Biological Chemistry 269 (1994): 105-113.
19. Zhao W., et al. “Dopamine receptors modulate cytotoxicity of natural killer cells via cAMP-PKA-CREB signaling pathway”. PLOS One 8 (2013): e65860.
20. Herzig S., et al. “CREB regulates hepatic gluconeogenesis through the coactivitor PGC-1”. Nature 413 (2001): 179-183.
21. Klemm DJ., et al. “Insulin stimulates cAMP-response element binding protein activity in HepG2 and 3T3-L1 cell lines”. Journal Biological Chemistry 273 (1998): 917-923.
22. Casadio A., et al. “A transient neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis”. Cell 99 (1999): 221-237.
23. Martin KC., et al. “Synapse-specific long-term facilitation of aplysis sensory to motor synapses. A function for local protein synthesis in memory storage”. Cell 91 (1997): 927-938.
24. Ignarro LJ., et al. “Activation of purified soluble graylate cyclase by protoporphyrin IX”. Proceeding National Academic Sciences 79 (1982): 2870-2873.
25. Matsuoka G., et al. “Localization of adenyyl and guanylyl cyclase in rat brain by in situ hybridization comparison with calmodulin mRNA distribution”. Neuroscience 12 (1992): 3350-3360.
26. Sanchez JJ., et al. “Sodium nitroprusside stimulated L-DOPA release from striatal tissue through nitric oxide and cGMP”. European Journal Pharmacology 438 (2002): 79-83.
27. Lu YF and Hawkins RD. “Ryanodine receptors contribute to cGMP-induced late-phase LTP and CREB phosphorylation in the hippocampus”. Journal Neurophysiology 88 (2002): 1279-1278.
28. Mattson MP. “Pathways towards and away from Alzheimer’s disease”. Nature 430 (2004): 631-639.
29. Huang CL and Kuo E. “Mechanisms of disease: WNK-ing at the mechanism of salt-sensitive hypertension”. Nature Clinical Practice Nephrology 3 (2007): 623-630.
30. Do QD., et al. “Redox dysregulation, neurodevelopment, and schizophrenia”. Current Opinion Neurobiology 19 (2009): 220-230.
31. Nomikos M., et al. “Phospholipase Cζ rescues failed oocyte activation in a prototype of male factor infertility”. Fertility Sterility 99 (2013): 76-85.
32. Gold MG., et al. “Local cAMP signaling in disease at a glance”. Journal Cell Science20 (2013): 4537-4543.
33. Schmidt D and Dent G. “Selective phosphodiesterase inhibitors for the treatment of bronchial asthma and chronic obstructive pulmonary disease”. Clinical Experimental Allergy2 (1999): 99-109.
34. Martı́nez M., et al. “Increased cerebrospinal fluid cAMP levels in Alzheimer’s disease”. Brain Research2 (1999): 265-267.
35. Fajardo AM., et al. “The role of cyclic nucleotide signaling pathways in cancer: targets for prevention and treatment”. Cancers1 (2014): 436-458.
36. Moore RH., et al. “Salmeterol stimulation dissociates β2-adrenergic receptor phosphorylation and internalization”. American Journal Respiratory Cell Molecular Biology2 (2007): 254-261.
37. Francis SH., et al. “Inhibition of cyclic nucleotide phosphodiesterases by methylxanthines and related compounds”. Handbook Experimantal Pharmacology 200 (2011): 93-133.
38. Moses AM., et al. “Antidiuretic and PGE2 responses to AVP and dDAVP in subjects with central and nephrogenic diabetes insipidus”. American Journal Physiology3 Pt 2 (1985): F354-359.
39. Feldman M and Burton ME. “Histamine-2-receptor antagonists: standard therapy for acid-peptic diseases”. New England Journal Medicine24 (1990): 1672-1680.
40. Muller MJ and Baer HP. “Relaxant effects of forskolin in smooth muscle: Role of cyclic AMP”. Naunyn-Schmiedeberg's Archives of Pharmacology 322 (1983): 78-82.
41. Behey E., et al. “The phosphodiesterase inhibitors pentoxifylline and rolipram suppress macrophages activation and nitric oxide production in vitro and in vivo”. Clinical Immunology 98 (2001): 272-279.
42. Lipworth BJ. “Phosphodiesterase -4-inhibitors for asthma and chronic obstructive pulmonary disease”. Lancet 365 (2005): 167-175.
43. Dastidar SG., et al. “Therapeutic benefit of PDE-4 inhibitors in inflammatory diseases”. Current Opinion Investigational Drugs 8 (2007): 364-372.
44. Kwok T., et al. “Helicobacter exploits integrin for type IV secretion and kinase activation”. Nature 449 (2007): 862-866.
45. Bristow MR. “Beta-adrenergic receptor blockade in chronic heart failure”. Circulation5 (2000): 558-569.
46. Bernstein MA and Welch SP. “mu-Opioid receptor down-regulation and cAMP-dependent protein kinase phosphorylation in a mouse model of chronic morphine tolerance”. Molecular Brain Research2 (1998): 237-242.
47. Niisato N., et al. “Effects of PKA inhibitors, H-compounds, on epithelial Na channels via PKA-independent mechanisms”. Life Science 65 (1999): PL109-PL114.
48. Ergenor OV., et al. “NO-independent stimulators and activators of soluble guanylate cyclase discovery and therapeutic potential”. Nature reviews. Drug Discovery 5 (2006): 755-768.
49. Kukreja RC., et al. “Cyclic guanosine monophosphate signaling and phosphodiesterase-5 inhibitors in cardioprotection”. Journal American College Cardiologist22 (2012): 1921-1927.
50. Kukreja RC. “Phosphodiesterase-5 and retargeting of subcellular cGMP signaling during pathological hypertrophy”. Circulation8 (2012): 916-919.
51. Ghofrani HA., et al. “Patent-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension”. New England Journal Medicine 369 (2013): 330-340.
52. Erdmann E., et al. “Cinaciguat, a soluble guanylate cyclase activator, unloads the heart but also causes hypotension in acute decompensated heart failure”. European Heart Journal 34 (2013): 57-67.