Transcript ATP as an Extracellular Signal

Cell Signaling, Wound Repair,
and ATP Receptors
Kevin Quirke and Alex Knobloch
Cell Signaling Overview
• typical cell exposed to numbers of different
signal molecules
– selective response according to cell function
– cellular response dictated by:
• unique sets of cell surface receptors
• cell-specific intracellular targets
Cell Signaling Overview
altered
metabolism
altered gene
expression
altered cell shape or
movement expression
Essential Cell Biology, 2nd
Edition (Alberts et al.,
2004)
Examples of Cell Signals
• growth/mitotic signaling:
epidermal growth factor (EFG)
EFG-receptor (EGFR)
EFG-receptor (EGFR)
Essential Cell Biology, 2nd
Edition (Alberts et al.,
2004)
Examples of Cell Signals
• growth/mitotic signaling:
EFG
activated EFGreceptor (EGFR)
Essential Cell Biology, 2nd
Edition (Alberts et al.,
2004)
Examples of Cell Signals
• growth/mitotic signaling:
active Ras
protein
phosphorylation
cascade
activation of
transcription factors for
pro-mitotic genes
Essential Cell Biology, 2nd
Edition (Alberts et al.,
2004)
Process Where Cell Signaling is
Important
=
Wound Repair
Wound Repair
• Tissue repair following injury
• Three phases6:
1. Inflammatory
2. Proliferative
3. Remodeling
Examples of Signals in
Inflammatory Phase
• PAMPs
• DAMPs
PAMPs
• Pathogen-associated molecular patterns
(PAMPs)
• Microbial molecules targeted by
macrophages
Bacterial Cell
Teichoic acid
Innate Immune Response to
PAMPs
PAMP
bacterium
Receptor
cytokines
macrophage
Inflammation
DAMPs
• Damage-associated molecular-patterns
(DAMPs)
• Intracellular molecules
• Released by cells undergoing stress or death
• Initiate immune response
Extracellular DNA as a DAMP
Extracellular Space
Extracellular DNA as a DAMP
Receptor
cytokines
Extracellular Space
macrophage
Inflammation
Key Recipient and Producer of
Inflammatory Phase Signals =
Monocytes
Monocyte
University of New England
•
•
•
•
White blood cell
Produced in boned marrow
Differentiates in tissues
Participate in wound repair
Phagocytes
Bone Marrow
Stem Cell
Blood
Monocyte
Tissue
Macrophage
Abbas et al., 2009
Monocyte’s Role in Wound
Repair
• Three phases:
1. Inflammatory
2. Proliferative
3. Remodeling
Monocyte’s Role in Wound
Repair
1. Produce inflammatory mediators
2. Produce pro-angiogenic factors
3. Phagocytose cellular debris
cytokines
monocyte
Pro-angiogenic factors
monocyte
monocyte
VEGF
•
•
•
•
Vascular endothelial growth factor
(VEGF)
Chemical signal
Pro-angiogenic factor
Promotes wound repair
VEGF’s Role in Wound Repair
• Three phases:
1. Inflammatory
2. Proliferative
3. Remodeling
VEGF’s Role in Wound Repair
• Promotes:
Endothelial cell
1. New blood vessel
formation (angiogenesis)
2. Endothelial cell proliferation
3. Oxygen supply to tissues
www.evgn.org
VEGF
• Triggers of VEGF production:
1. Hypoxia
2. Oncogenes
3. Other growth factors and
cytokines
4. Cellular receptors
Cell signal
VEGF
monocyte
• Trigger: Cellular receptor
• Target: Endothelial cell
VEGF Receptor
VEGF
VEGF receptor
Blood Vessel
ATP
=
one signal molecule to which
monocytes respond
ATP as an Extracellular Signal
• roles as signal molecule:
– DAMP
• inflammatory response1, pain sensation2
– synaptic signaling (neurotransmitter)2,3
– neuron-glia signaling4
– muscle contraction5
adenosine-5'-triphosphate
(ATP)
P2 Nucleotide Receptors
• family of nucleotide cell surface receptors
• two major subfamilies
P2Y Receptors
- G-protein coupled1
- bind ATP, ADP, UTP, and
UDP1
Essential Cell Biology, 2nd
Edition (Alberts et al.,
2004)
P2 Nucleotide Receptors
• family of nucleotide cell surface receptors
• two major subfamilies
P2Y Receptors
P2X Receptors
- G-protein coupled1
- ionotrophic (ligand-gated)1
- bind ATP, ADP, UTP, and
- bind ATP1
UDP1
wikipedia.org
P2X Subfamily
• ligand-gated ion channels
• cation selective2
– equal permeability to K+ and Na+
– significant permeability to Ca2+
• seven members (P2X1-7)
P2X7
• aka P2RX7
P2X7
• aka P2RX7
Zebrafish P2X4 (Kawate et al., 2009)
P2X7
• aka P2RX7
wikipedia.org
P2X7
• ligand-gated ion channel
ATP
Essential Cell Biology, 2nd
Edition (Alberts et al.,
2004)
P2X7
• requires high concentrations (mM) of ATP
for activation1
• sensitive to synthetic ATP analog BzATP1
3′-0-(4-benzoyl) benzoyl ATP
(BzATP)
O
O
P
O
O
O
P
O
O
O
P
N
N
O
N
N
O
O
O
O
H2 N
OH
O
adenosine-5'-triphosphate
(ATP)
P2X7
• requires high concentrations (mM) of ATP
for activation1
• sensitive to synthetic ATP analog BzATP1
3′-0-(4-benzoyl) benzoyl ATP
(BzATP)
O
O
P
O
O
O
P
O
O
O
P
N
N
O
N
N
O
O
O
O
H2 N
OH
O
adenosine-5'-triphosphate
(ATP)
P2X7
• major immune modulator
• activation in monocytes
production of pro-inflammatory
molecules
IL-1β
nitric oxide
synthase
ROS
(Lenertz et al.,
2009)
• The Hill et al. paper suggests a role for
ATP and P2X7 in the proliferative phase of
wound repair
– Counterintuitive considering its role in the
inflammatory phase…
P2RX7
ATP
monocyte
Cell
Angiogenesis
VEGF
References
1. Lenertz, L.Y., M.L. Gavala, L.M. Hill, and P.J. Bertics. 2009. Cell signaling
via the P2X7 nucleotide receptor: linkage to ROS production, gene
transcription, and receptor trafficking. Purinergic Signal 5: 175-187.
2. Khakh, B.S. 2001. Molecular physiology of P2X receptors and ATP signalling
at synapses. Nat. Rev. Neurosci. 2: 165-174.
3. Khakh, B.S., and R.A North. 2006. P2X receptors as cell-surface ATP
sensors in health and disease. Nature 442: 527-532.
4. Fields, R.D., and G. Burnstock. 2006. Purinergic signalling in neuron-glia
interactions. Nat. Rev. Neurosci. 7: 423-436.
5. Vassort, G. 2001. Adenosine 5′-triphosphate: a P2-purinergic agonist in the
myocardium. Physiol. Rev. 81: 767-806.
6. Kirsner, R.S., and W.H. Eaglstein. 1993. The wound healing process.
Dermatol. Clin. 11: 629-640.
7. Abbas, A.K., and A.H. Lichtman. 2009. Basic immunology: functions and
disorders of the immune system. Saunders: Philadelphia, pp. 24-29.