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Min-Chuan Huang
1
Intracellular messenger substances: second messengers
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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
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Intracellular messenger substances: second messengers
3 modified from Biochemistry of Signal Transduction and Regulation. 2008. 4th ed. Gerhard Kraus
Gases: NO CO H2S
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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
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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
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Transmembrane (tm)AC and soluble (s)AC
6 Kidney International (2011) 79, 1277–1288
HCO3-
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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
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8 Pharmacol Rev. 2013 Feb 27;65(2):670-709.
Targets of cAMP
1.
2.
3.
4.
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9
PKA
cAMP activates PKA
Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
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Epac is cAMP-dependent GEF for Rap
10 Br J Pharmacol. 2010 Jan 1;159(2):265-84.
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cGMP
• Guanylyl cyclase synthesizes cGMP from GTP.
• Two groups of guanylyl cyclases: – Guanylyl cyclase receptors
– soluble guanylyl cyclases
• Phosphodiesterase degrades cGMP to GMP.
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• Activated by extracellular peptide ligands: atrial natriuretic peptide
• Single transmembrane protein
• Synthesize cGMP in an ATP-dependent manner
12
Guanylyl cyclase receptors
Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
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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
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Molecular Cell Biology, 2013. 7th ed. Lodish
NO receptor = soluble guanylyl cyclase (sGC)
14
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Targets of cGMP
• PKG
• cGMP-gated cation channels
• cAMP-dependent PDEs
15
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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)
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Phosphatidylinositol-derived messengers
• DAG
• IP3
• IPx
• PI(3,4,5)P3
• PIPx
18
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19 Molecular Cell Biology, 2008. 6th ed. Lodish
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Key enzymes of PtdIns metabolism
• PLCβ and PLCγ
• PI3K
• Phosphoinositide phosphatases
20
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21
RTK vs. GPCR PLCγ vs. PLCβ
Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
Gq
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22 Molecular Cell Biology, 2013. 7th ed. Lodish
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23 Molecular Cell Biology, 2013. 7th ed. Lodish
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(Akt) PDK2 (Akt) (Akt)
Molecular Cell Biology, 2013. 7th ed. Lodish
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25 Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
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DAG as a signal molecule
26
- Formed from PIP2 - Activates PKC - Source of arachidonic acid
Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
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Other lipid messengers • Ceramide
• Sphingosine-1-phosphate (S1P)
• Lysophosphatidic acid (LPA)
• Platelet activating factor (PAF)
• Arachidonoyl ethanolamine (AEA)
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Ca2+ as a signal molecule
• Muscle contraction
• Vision process
• Cell proliferation
• Secretion
• Cell motility
• Formation of cytoskeleton
• Gene expression
28
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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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30
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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31
Opening of Ryanodine receptors and IP3 receptors by: IP3, Ca2+, cADP ribose, NAADP
Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus cADPR
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Ca2+ release
32 Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
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How Ca2+ works?
• Direct activation of enzymes – PKC
– PLA2
– PLCγ
• Binding to Ca2+ sensors – Calmodulin
– Troponin C
– Recoverin 33
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Mechanisms of activation of target proteins by Ca2+ / calmodulin
34 Biochemistry of Signal Transduction and Regulation. 4th ed. Gerhard Kraus
... .. --. -. .- .-.. / - .-. .- -. ... -.. ..- -.-. - .. --- -.
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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
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NO-sensitive guanylyl cyclase
36 Handb Exp Pharmacol. 2009;(191):17-31.
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37 Circ Res. 2010 Mar 5;106(4):633-46.
S-nitrosylation
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Protein denitrosylation:
38
Trx/TrxR and GSH/GSNOR systems
Nat Rev Mol Cell Biol. 2009 Oct;10(10):721-32.
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39 Nature Reviews Molecular Cell Biology 10, 721-732 (October 2009)
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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.
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Interactions between the three gas-generating systems
41 Nat Rev Drug Discov. 2010 Sep;9(9):728-43.
Haem oxygenase 1
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Major sites of reactive oxygen species (ROS)
42 Nat Rev Drug Discov. 2009 Jul;8(7):579-91.
(superoxide)
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Mechanisms of ROS effects on protein functions
43 Nat Rev Drug Discov. 2009 Jul;8(7):579-91.