CELL SIGNALING Lecture 1

1
CELL SIGNALINGLecture 1
2
Course Contents

• Overview of cell signaling
• Principles of cell signaling
• Types of ligands and receptors
• Signaling through enzyme liked cell-surface
  receptors
• Receptor tyrosine kinases and non-receptor
  tyrosine kinases
• Signaling via receptor tyrosine kinases
• Signaling via tyrosine kinase associated
  receptors
• Signaling via receptor serine-/threonine kinases
  
• Signaling through G protein linked receptors
• Small GTPases
• G protein coupled receptors
• Lipid (2nd messengers)-mediated cell signaling
• Synaptic signaling

3

• ATP-signaling
• Purinergic (P2X and P2Y) signaling
• iNOS signaling
• Cell adhesion molecules
• Plant cell signaling (role of growth factors,
  hormones and pheromones)
• Plant defense mechanism
• Signaling in microbes
• BOOKS RECOMMENDED
• Molecular Biology of the Cell by Bruce Albert and
  Dennis Bray, 4th Ed. Garland Publishing Inc, New
  York and London
• Handbook of Cell Signaling Vol 1-3, by Ralph
  Bradshaw, and Edward Dennis
• Signal Transduction by Bastien D. Gomperts
• The Biochemistry of Cell Signalling (Paperback)by
  Ernst J. M. Helmreich

4
INTRODUCTION

• No cell lives in isolation
• Eukaryotic organisms like yeast and molds also
  secrete molecules known as Pheromones
• Higher animals secrete extracellular molecules
  that function within an organism
• Ligand
• Receptor
• The overall process of converting signals into
  cellular responses as well as the individual
  steps in this process is termed as SIGNAL
  TRANSDUCTION

5
GENERAL PRINCIPLES OF CELL SIGNALING
6
Extracellular Signaling Molecules are Recognized
by Specific Receptors on or in Targets Cells

• Cells in higher animals communicate through
  hundreds of signalling molecules, including
• Proteins
• Small peptides
• Amino acids
• Nucleotides
• Steroids
• Retinoids
• Fatty acids derivatives and even
• Gases like nitric oxide and carbon monoxide

7

• Most of these molecules are secreted by the
  signaling cell through
• Exocytosis
• Diffusion through plasma membrane, or
• Remain tightly bound to the cell surface

8
(No Transcript)
9

• Regardless of the nature of the signaling
  molecule, the target cell responds by means of a
  specific protein known as the RECEPTOR
• Extracellular signaling molecules act at very low
  concentrations ( lt 10 -8 M)
• While the receptors that recognize them bind them
  with very high affinity
• In most cases the receptors are transmembrane
  proteins that upon activation trigger a cascade
  of signaling events
• However some receptors lie inside the cell
• And the LIGAND needs to diffuse inside the cell
  to activate it
• In these cases the ligand is usually a small and
  hydrophobic molecule

10
(No Transcript)
11
Secreted Molecules Mediate 3 Forms of Signaling

• Paracrine,
• Synaptic and
• Endocrine
• Type of signaling path mediated depends upon the
  distance that the signaling molecule is required
  to cover

12
Paracrine Signaling
13

• The secreted molecule must not be allowed to
  diffuse too far
• Often rapidly taken up by target neighboring
  cells
• Destroyed by extracellular enzymes, or
• Immobilized by extracellular matrix

14
Synaptic Signaling

• Sets of specialized cells have evolved with a
  specific role in signaling between widely
  separated parts of the body of complex organisms
• Most sophisticated are the nerve cells
• Upon activation the signal is transmitted in the
  form of action potential as an electrical impulse
• At the nerve terminal a chemical signal
  (neurotransmitter) is released
• The signal is transmitted through special cell
  junctions known as Chemical Synapses

15
(No Transcript)
16
Endocrine Signaling

• Another example of specialized cells operating
  over a distance are endocrine cells
• Secrete signaling molecules known as HORMONES
• Into the blood stream (animals) or
• The sap (plants)

17
(No Transcript)
18
Contrast

• Endocrine signaling is slow since it relies on
  diffusion and blood flow
• Nerve cells can achieve much higher speed and
  precision
• 100 meters per second
• A neurotransmitter has to diffuse less than 100nm
  to the target cell
• This process takes less than a millisecond
• Hormones are greatly diluted and act at very low
  concentrations while neurotransmitters can
  achieve high local concentrations
• Acetylcholine concentration at a synaptic cleft
  can reach a conc. of 5 x 10 -4 M
• Correspondingly neurotransmitter receptors have
  low affinity for their ligands as compared to
  hormones

19
(No Transcript)
20
Autocrine Signaling can Coordinate Decisions by
Groups of Identical Cells

• Cells not only communicate to other types of
  cells but also to their own types
• And can also send signals to themselves
• AUTOCRINE SIGNALING
• Thus a secreted molecule can bind receptors on
  the cell itself
• When carried out simultaneously by neighboring
  cells, autocrine signaling can direct cells to
  take the same decision e.g during differentiation
  (developmental decisions)
• Also known as COMMUNITY EFFECT

21
(No Transcript)
22

• Eicosanoids are molecules secreted in mature
  mammals
• Are fatty acid derivatives
• There are four major classes of eicosanoids -
• prostaglandins, prostacyclins, thromboxanes,and
  leukotrienes
• Are continuously synthesized in the plasma
  membrane and released to the cell exterior
• Where they are degraded by enzymes
• Involved in various biological activities
• Contraction of smooth muscles
• Aggregation of platelets
• Pain and inflammatory responses
• It has been observed that in case of tissue
  damage or any other chemical signal the rate of
  eicosanoid synthesis increases
• Influencing both the synthesizing cell and also
  its neighbors

23
(No Transcript)
24

• The synthesis of all but the leukotrienes
  involves the enzyme cyclooxygenase the synthesis
  of leukotrienes involves the enzyme lipoxygenase
• These synthetic pathways are targets for a large
  number of therapeutic drugs, since eicosanoids
  play an important part in pain, fever, and
  inflammation
• Corticosteroid hormones such as cortisone, which
  inhibit the activity of the phospholipase in the
  first step of the eicosanoid synthesis pathway,
  are widely used clinically to treat noninfectious
  inflammatory diseases
• Nonsteroid anti-inflammatory drugs such as
  aspirin and ibuprofen, by contrast, block the
  first oxidation step, which is catalyzed by
  cyclooxygenase.
• Certain prostaglandins that are produced in large
  amounts in the uterus at the time of childbirth
  to stimulate the contraction of the uterine
  smooth muscle cells are widely used as
  pharmacological agents to induce abortion.