2.9 - Cell Signalling

Question 1

Why do cells need to communicate?

Answer 1

1. to process information (sensory stimuli e.g. light and sound)
2. self-preservation (identify danger and take appropriate actions e.g. spinal reflexes and sympathetic NS) - innate
3. voluntary movement
4. homeostasis (e.g. thermoregulation, BGC)

Question 2

Endocrine signalling

Answer 2

Hormone travels within blood vessels to act on a distant target cell

• e.g. glucagon is secreted by alpha cells of Islets of Langerhans and travels out of pancreas in blood vessels, stimulating gluconeogenesis and glycogenolysis within the liver = increased BGC
• e.g. insulin produced in the pancreas acts on the liver, muscle cells and adipose tissue
• e.g. adrenaline produced in the adrenal glands acting on the trachea

Question 3

Paracrine signalling

Answer 3

Hormone acts on an adjacent cell

• e.g. insulin produced by beta cells in response to hyperglycaemia acts on alpha cells to inhibit glucagon secretion
• e.g. nitric oxide produced by endothelial cells in blood vessels, acts on smooth muscle cells = vasodilation
• e.g. osteoclast activating factors produced by adjacent osteoblasts

Question 4

Signalling between membrane-attached proteins

Answer 4

Plasma membrane proteins on adjacent cells interacting

• e.g. TCR interacting with MHC class II molecule - blood borne virus detected within bloodstream by APC, which digests pathogen = expresses MHC class II molecules on surface, circulating T cell engages with MHC through TCR interaction
• e.g. HIV GP120 glycoprotein interacts with CD4 receptor on T cells
• e.g. bacterial cell wall components binding to toll-like receptors on haematopoietic stem cells

Question 5

Autocrine signalling

Answer 5

Signalling molecule acts on same cell

• involved in positive or negative feedback
• e.g. interleukin-2 acting on T lymphocytes - activated T cell expresses interleukin-2 which binds to IL-2 receptor on same cell
• e.g. acetylcholine acting on presynaptic M2 muscarinic receptors
• e.g. growth factors (e.g. TGFB) from tumour cells leading to mitogenesis

Question 6

Neurotransmission (intracellular signalling)

Answer 6

1. Propagation of action potential
   - AP propagated by VGSCs opening
   - Na+ influx –> membrane depolarisation –> AP ‘moves along’ neurone
   - VGKC opening –> K+ efflux –> repolarisation
2. NT release from vesicles
   - AP opens voltage-gated Ca2+ channels at presynaptic terminal
   - Ca2+ influx –> vesicle exocytosis
3. Activation of postsynaptic receptors
   - NT binds to receptors on postsynaptic membrane
   - receptors modulate postsynaptic activity
   - the signal can be transmitted by a variety of different types of receptor

Question 7

Ionotropic receptor

Answer 7

1. ligand (molecule which binds to receptor) binds to receptor protein
2. change in conformation of channel protein –> opening of pore
3. pore allows ions to move in and out of cell according to their respective concentration gradients

• e.g. nicotinic acetylcholine
• ligand - acetylcholine
• location - skeletal muscle
• physiological effect - muscle contraction

Question 8

G-protein coupled receptor

Answer 8

• ligand binding –> activates intracellular G protein
  1. in resting state the G protein complex consists of a Ga subunit, GBy subunit and an associated GDP molecule, which are in close proximity to the receptor. 7-transmembrane receptor and heterotrimeric G-protein are inactive
  2. ligand binding –> changes conformation of receptor
  3. unassociated G-protein binds to the receptor –> GDP is exchanged for GTP (allows heterotrimer to dissociate)
  4. G-protein dissociates into two active components: a-subunit and By subunit (GTP stays attached to alpha component). They bind to their target proteins and both can act as second messengers
  5. internal GTPase activity on a-subunit dephosphorylates GTP –> GDP
  6. a-subunit dissociates from target protein –> inactive again = heterotrimer reformed as Ga and GBy reassociate
  7. receptor remains active as long as ligand is bound and can activate further heterotrimeric G-proteins

Question 9

Examples of G-protein coupled receptors

Answer 9

1. Gs protein linked receptor - stimulates adenylyl cyclase
   - converts ATP to cAMP, which activates protein kinase A (PKA)
   - e.g. B1-adrenergic receptor (fight / flight)
2. Gi protein linked receptor - inhibits adenylyl cyclase
   - reduces levels of PKA
   - e.g. M2-muscarinic receptor (rest / digest)
3. Gq protein linked receptor - stimulates phospholipase C (PLC)
   - converts PIP2 –> IP3 + DAG
   - IP3 stimulates CA2+ release
   - DAG activates PKC
   - e.g. AT-1 angiotensin receptor

Question 10

Enzyme-linked receptor

Answer 10

1. ligand binding –> receptor clustering
2. activates internal enzyme activity within cytoplasmic domain
3. enzymes phosphorylate receptor
4. phosphorylation –> binding of signalling proteins to cytoplasmic domain
5. these signalling proteins –> recruit other signalling proteins –> signal is generated –> cascade

• e.g. insulin receptor (CD220 antigen): ligand - insulin; physiological effect - glucose uptake
• e.g. ErbB receptors: ligand - epidermal growth factor, transforming growth factor B; physiological effect - cell growth and proliferation

Question 11

Intracellular receptor - Type 1

Answer 11

• a membrane permeable ligand binds to receptor inside cell
  Type 1 - cytoplasmic
  1. located within cytosolic compartment
  2. associated with chaperone molecules (heat shock proteins / HSP)
  3. hormone binds to receptor –> HSP dissociates
  4. two hormone bound receptors form a homodimer
  5. the homodimer translocates to the nucleus –> binds to DNA
• e.g. glucocorticoid receptor
• ligands: cortisol, corticosterone
• physiological effect: reduced immune response, increased gluconeogenesis

Question 12

Intracellular receptor - Type 2

Answer 12

Type 2 - nuclear
1. located within the nucleus
2. binding of hormone ligand (directly to nucleus) –> transcriptional regulation

• e.g. thyroid hormone receptor
• ligand: thyroxine (T4), triiodothyronine (T3)
• physiological effect: growth and development