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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

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Cell signaling wound repair and atp receptors

Cell Signaling, Wound Repair, and ATP Receptors

Kevin Quirke and Alex Knobloch


Cell signaling overview
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 overview1
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
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 signals1
Examples of Cell Signals

  • growth/mitotic signaling:

EFG

activated EFG-receptor (EGFR)

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


Examples of cell signals2
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)



Wound repair
Wound Repair

Inflammatory

Proliferative

Remodeling

  • Tissue repair following injury

  • Three phases6:



Pamps
PAMPs

Pathogen-associated molecular patterns (PAMPs)

Microbial molecules targeted by macrophages

Bacterial Cell

Teichoic acid


Innate immune response to pamps
Innate Immune Response to PAMPs

PAMP

bacterium

Receptor

Inflammation

cytokines

macrophage


Damps
DAMPs

Damage-associated molecular-patterns (DAMPs)

Intracellular molecules

Released by cells undergoing stress or death

Initiate immune response


Extracellular dna as a damp
Extracellular DNA as a DAMP

Extracellular Space


Extracellular dna as a damp1
Extracellular DNA as a DAMP

Receptor

Inflammation

cytokines

Extracellular Space

macrophage



Monocyte
Monocyte Monocytes

White blood cell

Produced in boned marrow

Differentiates in tissues

Participate in wound repair

University of New England

Phagocytes

Bone Marrow Stem Cell

Blood Monocyte

Tissue Macrophage

Abbas et al., 2009


Monocyte s role in wound repair
Monocyte’s Role in Wound Repair Monocytes

  • Three phases:

  • Inflammatory

  • Proliferative

  • Remodeling


Monocyte s role in wound repair1
Monocyte’s Role in Wound Repair Monocytes

Pro-angiogenic factors

cytokines

monocyte

monocyte

monocyte

  • Produce inflammatory mediators

  • Produce pro-angiogenic factors

  • Phagocytose cellular debris


VEGF Monocytes

Vascular endothelial growth factor (VEGF)

Chemical signal

Pro-angiogenic factor

Promotes wound repair


Vegf s role in wound repair
VEGF’s Role in Wound Repair Monocytes

  • Three phases:

  • Inflammatory

  • Proliferative

  • Remodeling


Vegf s role in wound repair1
VEGF’s Role in Wound Repair Monocytes

  • Promotes:

Endothelial cell

  • New blood vessel formation (angiogenesis)

  • Endothelial cell proliferation

  • Oxygen supply to tissues

www.evgn.org


VEGF Monocytes

Triggers of VEGF production:

  • Hypoxia

  • Oncogenes

  • Other growth factors and cytokines

  • Cellular receptors


VEGF Monocytes

Cell signal

monocyte

  • Trigger: Cellular receptor

  • Target: Endothelial cellVEGF Receptor

VEGF

VEGF receptor

Blood Vessel


Atp one signal molecule to which monocytes respond
ATP Monocytes= one signal molecule to which monocytes respond


Atp as an extracellular signal
ATP as an Extracellular Signal Monocytes

  • 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
P2 Nucleotide Receptors Monocytes

  • 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 receptors1
P2 Nucleotide Receptors Monocytes

  • 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
P2X Subfamily Monocytes

  • ligand-gated ion channels

  • cation selective2

    • equal permeability to K+ and Na+

    • significant permeability to Ca2+

  • seven members (P2X1-7)


P2x 7
P2X Monocytes7

  • aka P2RX7


P2x 71
P2X Monocytes7

  • aka P2RX7

Zebrafish P2X4 (Kawate et al., 2009)


P2x 72
P2X Monocytes7

  • aka P2RX7

wikipedia.org


P2x 73
P2X Monocytes7

  • ligand-gated ion channel

ATP

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


P2x 74
P2X Monocytes7

  • requires high concentrations (mM) of ATP for activation1

  • sensitive to synthetic ATP analog BzATP1

3′-0-(4-benzoyl) benzoyl ATP (BzATP)

adenosine-5'-triphosphate (ATP)


P2x 75
P2X Monocytes7

  • requires high concentrations (mM) of ATP for activation1

  • sensitive to synthetic ATP analog BzATP1

3′-0-(4-benzoyl) benzoyl ATP (BzATP)

adenosine-5'-triphosphate (ATP)


P2x 76
P2X Monocytes7

  • major immune modulator

  • activation in monocytes

production of pro-inflammatory

molecules

nitric oxide synthase

ROS

IL-1β

(Lenertz et al., 2009)



P2RX7 Monocytes

monocyte

ATP

Cell

Angiogenesis

VEGF


References
References Monocytes

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.


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