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Min-Chuan Huang
1
Intracellular messenger substances: second messengers
Types of second messengers • Cytosolic:
– cAMP, cGMP, cGMP-AMP (Science. 2013 Feb 15;339:826)
– Inositol phosphates
– Ca2+
• Membrane-associated – DAG
– phosphatidylinositides
• Gases: – NO, CO, H2S 2
Intracellular messenger substances: second messengers
3 modified from Biochemistry of Signal Transduction and Regulation. 2008. 4th ed. Gerhard Kraus
Gases: NO CO H2S
cAMP
4
adenylyl cyclase phosphodiesterase
H2O
cAMP ATP AMP
Earl Wilbur Sutherland Jr. Nobel Prize in Physiology or Medicine
in 1971
β-Adrenergic receptor epinephrine
NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 3 | SEPTEMBER 2002 | 639-650
Adenylyl cyclases (transmembrane and soluble ACs)
• 10 known adenylate cyclases in mammals: ADCY1 -9 (transmembrane), ADCY10 (soluble)
• tmAC: regulated by Gα, Gβγ, Ca2+
• sAC: regulated by HCO3-
5
Molecular Cell Biology, 2013. 7th ed. Lodish
Transmembrane (tm)AC and soluble (s)AC
6 Kidney International (2011) 79, 1277–1288
HCO3-
Targets of cAMP 1. PKA
2. cAMP-specific phosphodiesterases (PDEs)
3. Ion channels
4. Epac : GEF for Rap
7
Epac: Exchange protein directly activated by cyclic AMP
8 Pharmacol Rev. 2013 Feb 27;65(2):670-709.
Targets of cAMP
1.
2.
3.
4.
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PKA
cAMP activates PKA
Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
Epac is cAMP-dependent GEF for Rap
10 Br J Pharmacol. 2010 Jan 1;159(2):265-84.
cGMP
• Guanylyl cyclase synthesizes cGMP from GTP.
• Two groups of guanylyl cyclases: – Guanylyl cyclase receptors
– soluble guanylyl cyclases
• Phosphodiesterase degrades cGMP to GMP.
11
• Activated by extracellular peptide ligands: atrial natriuretic peptide
• Single transmembrane protein
• Synthesize cGMP in an ATP-dependent manner
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Guanylyl cyclase receptors
Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
Soluble guanylyl cyclases
• Contain a heme group • Activated by NO (NO receptor) • Active form: heterodimer (α+β). In humans, it is
encoded by the genes GUCY1A2, GUCY1A3, GUCY1B2 and GUCY1B3 13
Trends Biochem Sci. 2006 Apr;31(4):231-9.
β subunit
Molecular Cell Biology, 2013. 7th ed. Lodish
NO receptor = soluble guanylyl cyclase (sGC)
14
Targets of cGMP
• PKG
• cGMP-gated cation channels
• cAMP-dependent PDEs
15
16 modified from Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
peptide
PDE
HCO3-
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Cyclic GMP-AMP (cGAMP) cGAMP synthase (cGAS)
Science. 2013 Feb 15;339:826 Science. 2013 Feb 15;339:786
Science 339, 763 (2013)
stimulator of interferon genes (STING)
Phosphatidylinositol-derived messengers
• DAG
• IP3
• IPx
• PI(3,4,5)P3
• PIPx
18
19 Molecular Cell Biology, 2008. 6th ed. Lodish
Key enzymes of PtdIns metabolism
• PLCβ and PLCγ
• PI3K
• Phosphoinositide phosphatases
20
21
RTK vs. GPCR PLCγ vs. PLCβ
Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
Gq
22 Molecular Cell Biology, 2013. 7th ed. Lodish
23 Molecular Cell Biology, 2013. 7th ed. Lodish
24
(Akt) PDK2 (Akt) (Akt)
Molecular Cell Biology, 2013. 7th ed. Lodish
25 Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
DAG as a signal molecule
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- Formed from PIP2 - Activates PKC - Source of arachidonic acid
Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
Other lipid messengers • Ceramide
• Sphingosine-1-phosphate (S1P)
• Lysophosphatidic acid (LPA)
• Platelet activating factor (PAF)
• Arachidonoyl ethanolamine (AEA)
27
Ca2+ as a signal molecule
• Muscle contraction
• Vision process
• Cell proliferation
• Secretion
• Cell motility
• Formation of cytoskeleton
• Gene expression
28
Storage and release of Ca2+
29 Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
10-3 M
10-7 - 10-8 M
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Ryanodine receptors and IP3 receptors
Skeletal muscle Cardiac muscle Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
Ryanodine receptor
Ryanodine receptor IP3 receptor
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Opening of Ryanodine receptors and IP3 receptors by: IP3, Ca2+, cADP ribose, NAADP
Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus cADPR
Ca2+ release
32 Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
How Ca2+ works?
• Direct activation of enzymes – PKC
– PLA2
– PLCγ
• Binding to Ca2+ sensors – Calmodulin
– Troponin C
– Recoverin 33
Mechanisms of activation of target proteins by Ca2+ / calmodulin
34 Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
... .. --. -. .- .-.. / - .-. .- -. ... -.. ..- -.-. - .. --- -.
35
NO as a signaling molecule
NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 6 | FEBRUARY 2005 | 151
Soluble guanylyl cyclase Hb
The Nobel Prize in Physiology or Medicine in 1998 : Ferid Murad, Robert F. Furchgott, and Louis Ignarro
NO-sensitive guanylyl cyclase
36 Handb Exp Pharmacol. 2009;(191):17-31.
37 Circ Res. 2010 Mar 5;106(4):633-46.
S-nitrosylation
Protein denitrosylation:
38
Trx/TrxR and GSH/GSNOR systems
Nat Rev Mol Cell Biol. 2009 Oct;10(10):721-32.
39 Nature Reviews Molecular Cell Biology 10, 721-732 (October 2009)
40
SNO Protein Disease State Serum albumin Preeclampsia
Ischemic coronary syndromes Hb Congestive heart failure
Pulmonary arterial hypertension Sickle cell disease Diabetes (type 1) Septic shock
HIF-1 Pulmonary arterial hypertension Matrix metalloproteinase 9 Stroke Ryanodine receptor 2 Arrhythmogenesis, Heart failure L-type Ca2+ channel (1C subunit) Atrial fibrillation/arrhythmia Cardiac Na+ channel SNC5a Long Q/T syndrome Slowly activating delayed-rectifier K+ channel
Atrial fibrillation/arrhythmia
Insulin receptor β Diabetes (type 2) Insulin receptor substrate 1 Diabetes (type 2) Akt (protein kinase B) Diabetes (type 2)
Aberrant S-Nitrosylation in Cardiovascular Disease
Circ Res. 2010 Mar 5;106(4):633-46.
Interactions between the three gas-generating systems
41 Nat Rev Drug Discov. 2010 Sep;9(9):728-43.
Haem oxygenase 1
Major sites of reactive oxygen species (ROS)
42 Nat Rev Drug Discov. 2009 Jul;8(7):579-91.
(superoxide)
Mechanisms of ROS effects on protein functions
43 Nat Rev Drug Discov. 2009 Jul;8(7):579-91.
