Week 2 Cell Signalling – direct & indirect II

Question 1

What are biogenic amines?

Answer 1

Organic molecules containing amine (NH2) – usually derived from an a.a.

• biogenic - naturally occuring
• Amines can accept protons with a positive charge

These are all made by amine group on the side chain of the amino acid (R Group)

Question 2

The a.a. Tyrosine (Tyr) gives rise to what biogenic amine?

Answer 2

Catecholamines (dopamine, octopamine, noradrenaline & adrenaline)

(hydrophilic)

Question 3

The a.a. Thyrosine derivative (Thyronine) gives rise to what biogenic amine?

Answer 3

Thyroid hormones (thyroxine)

(hydrophobic)

Question 4

The a.a. Tryptophan (Trp) gives rise to what biogenic amine?

Answer 4

Indoleamines (serotonin & melatonin)

(hydrophilic)

Question 5

The a.a. Histine (His) gives rise to what biogenic amine?

Answer 5

Histamine

(hydrophilic)

Question 6

The a.a. Choline (lipid) gives rise to what biogenic amine?

(hydrophilic)

Answer 6

Acetylcholine (ACh)

Question 7

What are Catecholamines?

Answer 7

• Hydrophilic (-OH group) derivatives of Tyrosine
• Dopamine = neurotransmitter (all taxa)
• Octopamine = neurotransmitter (invertebrate – protostomes)
• Noradrenaline (norepinephrine) = neurotransmitter (vertebrates)
• Adrenaline (epinephrine) = paracrine and endocrine hormone (vertebrates)
  
  • conversion of noradrenaline to adrenaline by PNMT enzyme – adrenal medulla only
• Inactivated by monoamine oxidases (MAO)

Question 8

What are Thyroid hormones?

Answer 8

• Hydrophobic derivatives of Tyrosine
• Thyroid follicles contain colloid – rich in thyroglobulin (Tg)
• Tg contains c.200 tyrosyl residues – metabolised by thyroid peroxidase:
  
  • • 1 iodine atom = monoiodotyrosine (MIT)
  • • 2 iodine atoms = diiodotyrosine (DIT)
  • couples 2 x DIT = tetraiodothyronine (T4) – thyroxine
  • couples 1 x DIT + 1 x MIT = triiodothyronine (T3)​
• Thyroid hormones unique to vertebrates (have to have a thyroid gland)
• Thyroid hormones are hydrophobic:
  
  • Low solubility in blood (<1% ‘free’ hormone)
  • T₄ (and T₃) interact with:
    
    • thyroxine-binding globulin (TBG) (70%)
    • albumen (15-20%)
    • transthyretin (15%)
• Activate nuclear receptors to increase BMR

Question 9

What are Indoleamines?

Answer 9

• Hydrophilic derivatives of tryptophan (Trp)
• Serotonin = 5-hydroxytryptamine (5HT)
• 5HT = neurotransmitter (all taxa) – acts via plasma membrane 5HT receptors
• Melatonin = metabolite of 5HT!
• Melatonin =
  
  • neurotransmitter (most taxa)
  • hormone (vertebrates) – mediates circadian and seasonal rhythyms – secreted from vertebrate pineal gland at night (measures changes in photoperiod)

Question 10

What are Histamines?

Answer 10

• Hydrophilic amine metabolite of Histidine
• Histamine = neurotransmitter and paracrine signalling molecule (all taxa) – acts via plasma membrane H1 / H2 / H3 / H4 receptors
• Vertebrates – acts as vasodilator and bronchoconstrictor – induces mast cell chemotaxis
• Allergens stimulate histamine release from mast cells and basophils – mediate allergic reaction

Question 11

What is Acetylcholine (ACh)?

Answer 11

• Hydrophilic amine metabolite of Choline
• ACh = primary neurotransmitter (all taxa)
• Acts via plasma membrane receptors:
  
  • Nicotinic ACh receptor (NAChR) = ionotropic receptor
  • Metabotropic ACh receptor (MAChR) = metabotropic receptor (GPCR)
• Receptors expressed at neuromuscular junctions, autonomic and central nervous systems

Question 12

What are Steroid hormones?

Answer 12

• 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 13

What are the 5 classes of Steriod hormone?

Answer 13

• 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

Question 14

Where are steriod hormones synthesised?

Answer 14

Synthesised in mitochondria + smooth ER

Question 15

What are the affects of steriod hormones being lipophilic?

Answer 15

• can’t be stored
• synthesised immediately prior to “secretion” (they are just released, they are not secreated)

Question 16

How do steriod hormones bind?

Answer 16

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

​needs carrier protein

Question 17

How do the laws of mass action & equilibrium work in steriod hormones?

Answer 17

Carrier proteins function by laws of mass action & equilibrium

M + C ⋛M-C

• M = messenger
• C = carrier
• M-C = messengercarrier
• complex

Question 18

What do steroid hormones bind to?

Answer 18

Classically bind “nuclear” receptors

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

Question 19

What do steroid hormones function as?

Answer 19

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)

Question 20

What are Eicosanoids Lipids?

Answer 20

• 20C lipids:
  
  • Cyclooxygenase (COX) products = prostaglandins (PG) and thromboxanes (TX)
  • Lipoxygenase (LOX) products = leukotrienes (LT’s), hydroxyeicosatetraenonic acids (HETE’s) and lipoxins
• Majority derived from arachidonic acid (AA) (C20:4) esterified to membrane phospholipid
• PLA2 liberates AA as a substrate for:
  
  • COX (PTGS) enzymes generate PG + TX
  • LOX enzymes generate LT’s + HETE’s

Question 21

What are Prostaglandins?

Answer 21

• Mediate inflammation & nociception
• Can inhibit PLA₂ (glucocorticoids) or COX (non-steroidal anti-inflammatory drugs / NSAID’s)
• PG’s have very specific effects – e.g. PGF_2α constricts smooth muscle (vasculature & myometrium) whereas PGE₂ relaxes smooth muscle (vasodilator)
• PG’s act via GPCR
• FP receptor for PGF_2α activates
  
  • G_q – PLC – IP₃ – Ca²⁺ plus DAG
• EP₂ and EP₄ receptors for PGE₂ activates
  
  • G_s – AC – cAMP
• Rapid effects – sec to min
• PG’s rapidly inactivated by PGDH (hydroxyl to ketone at C15) – limits range of action (autocrine/paracrine only)

Question 22

What are Purines?

Answer 22

Purines (adenine & guanine) exist as nucleosides (adenosine & guanosine) and nucleotides (e.g. AMP, ATP & GTP)

Question 23

What can purines act as (& Adenosine)?

Answer 23

Purines can act as neurotransmitters & neuromodulators (modulate neuronal response to other neurotransmitters) and autocrine / paracrine hormones

Adenosine acts via purinergic receptors:

• P1 & P2Y = GPCR
• P2X = ligand-gated ion channel

Question 24

What are the actions of Adenosine?

Answer 24

Adenosine (and e.c. ATP) exerts wide range of actions including:

• Neurotransmitter (excitatory – depolarises cells via ionotropic receptors)
• Lowers heart rate (negative chronotropic receptors on cardiac myocytes – vertebrates)
• Autocrine action to modulate activation of leukocytes in immune response
• Skeletal remodelling by osteoblasts and osteoclasts (vertebrates)

Question 25

What terminates the signal in purines?

Answer 25

Signal terminated by the metabolism of ectonucleotidases – hydrolyse purine nucleotides

Question 26

What are Gases?

Answer 26

• Signalling gases include carbon monoxide (CO) and hydrogen sulphide (HS)
• Best understood example = nitric oxide (NO): synthesised from L-Arg by NO synthase (NOS)
• NO very short half-life (2-30 sec) so autocrine / paracrine actions only:
  
  • paracrine signal in immune system
  • vasodilator (via soluble guanylate cyclase / cGMP action attenuated by sildenafil)
• Gas does not require plasma membrane receptor – diffuses into cell