cell signaling, wound repair, and atp receptors kevin quirke and alex knobloch

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

Essential Cell Biology, 2nd Edition (Alberts et al., 2004)

altered metabolism

altered gene expression

altered cell shape or movement expression

Examples of Cell Signals

• growth/mitotic signaling:epidermal growth factor (EFG)

EFG-receptor (EGFR) EFG-receptor (EGFR)



• growth/mitotic signaling:

activated EFG-receptor (EGFR)

EFG



• growth/mitotic signaling:active Ras

protein

activation of transcription factors for

pro-mitotic genes

phosphorylation cascade


Process Where Cell Signaling is Important

=Wound Repair

Wound Repair

1. Inflammatory

2. Proliferative

3. Remodeling

• Tissue repair following injury

• Three phases6:

Examples of Signals in Inflammatory Phase

• PAMPs

• DAMPs

PAMPs

• Pathogen-associated molecular patterns (PAMPs)

• Microbial molecules targeted by macrophages

Teichoic acid

Bacterial Cell

Innate Immune Response to PAMPs

macrophage

bacterium

PAMP

Receptor

cytokines 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

Receptor

Extracellular DNA as a DAMP

Extracellular Spacemacrophage

cytokines Inflammation

Key Recipient and Producer of Inflammatory Phase Signals =

Monocytes

Monocyte

• White blood cell• Produced in boned marrow• Differentiates in tissues• Participate in wound repair

Bone Marrow Stem Cell

Blood Monocyte

Tissue Macrophage

Phagocytes

Abbas et al., 2009

University of New England

Monocyte’s Role in Wound Repair

1. Inflammatory

2. Proliferative

3. Remodeling

• Three phases:

Monocyte’s Role in Wound Repair

1. Produce inflammatory mediators

2. Produce pro-angiogenic factors

3. Phagocytose cellular debris

monocyte

cytokines

monocyte

Pro-angiogenic factors

monocyte

VEGF

• Vascular endothelial growth factor (VEGF)

• Chemical signal• Pro-angiogenic factor• Promotes wound repair

VEGF’s Role in Wound Repair

1. Inflammatory

2. Proliferative

3. Remodeling

• Three phases:

VEGF’s Role in Wound Repair

Endothelial cell

1. New blood vessel formation (angiogenesis)

2. Endothelial cell proliferation3. Oxygen supply to tissues

• Promotes:

www.evgn.org

VEGF

• Triggers of VEGF production:

1. Hypoxia 2. Oncogenes3. Other growth factors and

cytokines4. Cellular receptors

VEGF

VEGF receptor

VEGF

monocyte

Blood Vessel

Cell signal

• Trigger: Cellular receptor

• Target: Endothelial cellVEGF Receptor

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

UDP1Essential Cell Biology, 2nd Edition (Alberts et al., 2004)

P2 Nucleotide Receptors

• family of nucleotide cell surface receptors

• two major subfamilies

P2Y Receptors

- G-protein coupled1

- bind ATP, ADP, UTP, and

UDP1

P2X Receptors

- ionotrophic (ligand-gated)1

- bind ATP1

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

P2X7

• requires high concentrations (mM) of ATP for activation1

• sensitive to synthetic ATP analog BzATP1

adenosine-5'-triphosphate (ATP)

O

N

NN

N

NH2

OPOPOPO

O O O

O O OOH

O

OO

3′-0-(4-benzoyl) benzoyl ATP (BzATP)

P2X7

• major immune modulator

• activation in monocytes

IL-1βnitric oxide synthase

ROS

production of pro-inflammatorymolecules

(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…

ATP

VEGF

Cell

P2RX7

Angiogenesis

monocyte

References1. 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.

cell signaling, wound repair, and atp receptors kevin quirke and alex knobloch

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