Week 2 Cell Signalling – direct & indirect II Flashcards
What are biogenic amines?
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)
The a.a. Tyrosine (Tyr) gives rise to what biogenic amine?
Catecholamines (dopamine, octopamine, noradrenaline & adrenaline)
(hydrophilic)
The a.a. Thyrosine derivative (Thyronine) gives rise to what biogenic amine?
Thyroid hormones (thyroxine)
(hydrophobic)
The a.a. Tryptophan (Trp) gives rise to what biogenic amine?
Indoleamines (serotonin & melatonin)
(hydrophilic)
The a.a. Histine (His) gives rise to what biogenic amine?
Histamine
(hydrophilic)
The a.a. Choline (lipid) gives rise to what biogenic amine?
(hydrophilic)
Acetylcholine (ACh)
What are Catecholamines?
- 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)
What are Thyroid hormones?
- 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
What are Indoleamines?
- 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)
What are Histamines?
- 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
What is Acetylcholine (ACh)?
- 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
What are Steroid hormones?
- 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
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What are the 5 classes of Steriod hormone?
- 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
Where are steriod hormones synthesised?
Synthesised in mitochondria + smooth ER
What are the affects of steriod hormones being lipophilic?
- can’t be stored
- synthesised immediately prior to “secretion” (they are just released, they are not secreated)
How do steriod hormones bind?
- Steroids bind:
- Binding globulins (e.g. CBG and SHBG)
- Albumen
- Same principle applies to thyroid hormones (and vitamin D / cholecalciferol
needs carrier protein
How do the laws of mass action & equilibrium work in steriod hormones?
Carrier proteins function by laws of mass action & equilibrium
M + C ⋛M-C
- M = messenger
- C = carrier
- M-C = messengercarrier
- complex
What do steroid hormones bind to?
Classically bind “nuclear” receptors
- cytosol (class I nuclear receptor)
- nucleus (class II nuclear receptor)
What do steroid hormones function as?
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)
What are Eicosanoids Lipids?
-
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
What are Prostaglandins?
- Mediate inflammation & nociception
- Can inhibit PLA2 (glucocorticoids) or COX (non-steroidal anti-inflammatory drugs / NSAID’s)
- PG’s have very specific effects – e.g. PGF2α constricts smooth muscle (vasculature & myometrium) whereas PGE2 relaxes smooth muscle (vasodilator)
- PG’s act via GPCR
-
FP receptor for PGF2α activates
- Gq – PLC – IP3 – Ca2+ plus DAG
-
EP2 and EP4 receptors for PGE2 activates
- Gs – 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)
What are Purines?
Purines (adenine & guanine) exist as nucleosides (adenosine & guanosine) and nucleotides (e.g. AMP, ATP & GTP)
What can purines act as (& Adenosine)?
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
What are the actions of Adenosine?
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)
What terminates the signal in purines?
Signal terminated by the metabolism of ectonucleotidases – hydrolyse purine nucleotides
What are Gases?
- 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
