Cell Signalling

Question 1

Why do cells signals?

Answer 1

• Growth
• Differentiation
• Motility
• Metabolism
• Division
• Absoption
• Secretion
• Death

In order to do any of these things communication is key

Question 2

How can cells communicate?

Answer 2

• direct and indirect

Question 3

What are the direct ways to signal?

Answer 3

• Gap junctions

- Juxtacrine signalling (adjacent)

Question 4

What are the indirect ways to signal?

Answer 4

• autocrine signalling (self)
• paracrine signalling (neighbouring)
• endocrine (at a distance - blood)
• neuronal signalling (at a distance - neurons)

Question 5

What are the different ways cells signal?

Answer 5

• hormones (adrenaliine, insulin, testosterone)
• growth factors (insulin-like growth factors)
• inflammatory molecules (cytokines, prostaglandins)
• neurotransmitters (acetylcholine, dopamine, GABA, noradrenaline)

Question 6

How are the signals received?

Answer 6

• Receptors

- proteins that bind to the signal molecule to induce a conformational change

Question 7

What are the type of receptors?

Answer 7

• Ion channels (e.g. nicotinic acetylcholine receptor)
• G-protein-coupled receptors (GPCR)
  (e. g. adrenoceptors, glucagon receptor)
• Enzymatic receptors (e.g. insulin and growth factor receptors)
• Nuclear receptors (e.g. thyroxine, vitamin D and steroid hormone receptors)

Question 8

Direct methods: What is gap junction signalling?

Answer 8

• Molecules exchanged between cells via gap junctions:
  6 connexin molecules form a connexon
  2 connexons form a gap junction (channel)

Question 9

Direct methods: What is juxtacrine signalling?

Answer 9

• Ligand in plasma membrane of signalling cell A (e.g. ephrin)
• Receptor in plasma membrane of adjacent target cell B (e.g. eph receptor)
• important for cell migration

Question 10

What is indirect signalling?

Answer 10

• Signalling cell produces a chemical messenger / signalling molecule
• In most cases, signalling molecule secreted into ECF / lymph / blood
• Signalling molecule transported over distance (short, medium or long) to target cell
• Signalling molecule acts as ligand for receptor on / in target cell
• Signalling molecule elicits cellular response in target cell

Question 11

Indirect methods: What is autocrine signalling?

Answer 11

• Cell produces a local ligand that acts back on the receptor in the same cell!
• Allows cell to sense extracellular environment (“biochemical radar”)

Question 12

Indirect methods: What is paracrine signalling?

Answer 12

• Cell produces a local ligand that acts on neighbouring cells
• Moves over short distances by diffusion (e.g. local recruitment of inflammatory cells by mast cells via histamine)

Question 13

Indirect methods: What is endocrine signalling?

Answer 13

• Cell-cell communication over long distances
• Signalling cell termed an endocrine cell
• Signalling molecules (hormones) transported in circulatory system – blood (or lymph)

Question 14

Indirect methods: What is neural signalling?

Answer 14

• Messages (nerve impulses) travel long distances but chemical messengers only travel short distances:
• Long distances – action potentials
• Synaptic transmission – signalling molecules

Question 15

What is the speed of communication for autocrine?

Answer 15

• shortest distance – msec to sec

Question 16

What is the speed of communication for paracrine?

Answer 16

• short distance – msec to sec

Question 17

What is the speed of communication for endocrine?

Answer 17

• long distance – sec to mins (can be hours to days!)

Question 18

What is the speed of communication for neural?

Answer 18

• long distance – msec only!

Question 19

What are some biophysical properties?

Answer 19

• Hydrophilic:
  
  • soluble in aqueous solutions (ECF / blood / lymph)
  • activate plasma membrane receptors
• Hydrophobic:
  
  • insoluble in aqueous solutions (soluble in lipids / lipophilic)
  • require globular transport proteins to solubilise in ECF / blood
  • activate intracellular (nuclear) receptors

Question 20

What are the 6 major classes of signalling molecules?

Answer 20

• peptides: hydrophilic
• amines: either
• steroids: hydrophobic
• lipids: hydrophobic
• purines: hydrophilic
• gases: hydrophilic

Question 21

What are the 3 major classes of all known hormones?

Answer 21

• peptides
• amines
• steroids

Question 22

What are peptides?

Answer 22

• Single amino acids act as neurotransmitters (e.g. Asp, Cys, Glu – latter decarboxylated to form GABA) – can be excitatory amino acids (EAA) or inhibitory amino acids (IAA)
• Peptides (2-200 aa) act as:
  
  • Neurotransmitters (e.g. endorphins [16/17/31 aa])
• Hydrophilic hormones (e.g. endorphins [16/17/31 aa], oxytocin [9 aa] and TRH [3 aa])

Question 23

…. peptides?

Answer 23

• Translated from mRNA in rough ER
• Subject to post-translation modifications (e.g. glycosylation) in rough ER and Golgi apparatus
• Packaged into secretory vesicles – released by exocytosis (membrane depolarisation)
  
  • Immediate (paracrine peptides – cytokines)
  • Storage (most peptide hormones & neurotransmitters)
• Soluble in ECF / blood / lymph – don’t require a carrier / transport protein

Question 24

What are some nonapeptide hormones?

Answer 24

Posterior pituitary nonapeptide hormones:
Oxytocin (OT)
(Arginine) Vasopressin (AVP)

Question 25

…. peptides?

Answer 25

• Act via cell surface / transmembrane receptors: conformational change – affects:
  
  • ion flux (ionotropic receptor)
  • enzymes (metabotropic receptors)
• Degraded by action of proteases / peptidases – dictates peptide ‘half-life’; generally short:
  
  • secs for simple peptides (e.g. TRH)
  • hours for glycoproteins (e.g. LH & hCG)
• Consequence: continued action dependent on continued synthesis

Question 26

What are biogenic amines?

Answer 26

Organic molecules containing amine (NH2) – usually derived from an amino acid

Question 27

What are steroid hormones?

Answer 27

• Derived from cholesterol – hydrophobic 27C
• Important class of endocrine / paracrine hormones in all vertebrates (e.g. sex steroids) and many invertebrates (e.g. ecdysone)
• Implicated as pheromones for communication

Question 28

What are the 5 classes of steroid hormone?

Answer 28

• Progestins (e.g. progesterone) – 21C
• Glucocorticoids (e.g. cortisol) – 21C
• Mineralocorticoids (e.g. aldosterone) – 21C
• Androgens (e.g. testosterone) – 19C
• Estrogens (e.g. estradiol) – 18C
• Synthesised in mitochondria + smooth ER
• Lipophilic:
• Can’t be stored
• Synthesised immediately prior to “secretion”

Question 29

How do steroid hormones function?

Answer 29

Steroids bind:

• Binding globulins (e.g. CBG and SHBG)
• Albumen
• Same principle applies to thyroid hormones (and Vitamin D/cholecalciferol)

Carrier proteins function by laws of mass action & equilibrium
M + C            M-C
M = messenger
C = carrier
M-C = messenger-carrier complex

Question 30

How do Steroid hormones function?

Answer 30

Classically bind “nuclear” receptors

• cytosol (class I nuclear receptor)
• nucleus (class II nuclear receptor)

Functions as ligand-dependent transcription factor – binds DNA – controls access of RNA polymerase to DNA template (via histone acetylation) – modulates transcription of genes in target cell – slow acting (hours to days)

Increasing evidence for rapid effects via plasma membrane steroid receptors (e.g. mitogenic effects of estrogens)