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4TH YEAR - CSIM2 > Cellular Biology > Flashcards

Cellular Biology Flashcards

1
Q

What are the 4 main types of cell signalling?

A
  1. Endocrine - hormones secreted into the blood to act on a receptor at a different site (eg. insulin)
  2. Paracrine - hormones secreted to act on adjacent target cell (eg. vWF)
  3. Autocrine - target site on same cell (eg. immune)
  4. Juxtacrine - signalling by direct cell-cell linkage, often through membrane associated substances (eg. gap junctions in cardiac myocytes)
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2
Q

What is signal transduction?

A
  1. Extracellular signalling molecule (ligand) binding to and activating a cell surface receptor, to form a receptor-ligand complex
  2. This elicits a physiological response in the cell, by way of GTPase switch proteins, kinases, phosphates and secondary messengers

THE FUNCTION OF THIS PATHWAY IS TO AMPLIFY THE RESPONSE

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3
Q

In terms of therapeutic targets of signal transduction, where is the best point in the signal to ‘interrupt’?

A

Higher up - it is best to target the receptor itself, in order to have a predictable response and avoid unwanted side effects

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4
Q

Give some examples of secondary messengers

A 
Ions (ca++)
Lipid derivatives
Carbohydrate derivatives
Nucelotides (cAMP, cGMP)
Proteins (Ras, JAK, Raf)
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5
Q

What are the 4 main types of cell-surface receptor?

A
  1. Direct ligand gated receptor channel (ION)
  2. G protein coupled receptor
  3. Tyrosine kinase linked receptor (ENZYME)
  4. Intracellular
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6
Q

How does a direct ligand gated receptor work?

A
  • Ligand binds to receptor
  • Conformational change
  • Ion influx through a channel in the receptor
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7
Q

Give some examples of ligand gated receptors?

A

Nicotinic Ach (dysfunctional in myasthenia gravis)
GABA receptors
Neurotransmitters (serotonin)

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8
Q

How does a G protein coupled receptor work?

A
  • Ligand binds to receptor
  • Conformational change
  • Causes activation of an associated G protein (GDP-GTP)
  • GTP binds to alpha subunit and activates it
  • Activated alpha dissociates from beta/gamma
  • Trigger secondary messengers such as cAMP
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9
Q

How many domains and subunits is a G protein coupled receptor composed of

A 
7 membrane spanning domains
3 subunits (alpha, beta, gamma)
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10
Q

Describe 3 specific G protein pathways

A
  1. Gas
    - activates adenylyl cyclase
    - generates cAMP
    - activates protein kinase
    - signal activation
    - causes positive inotropy
  2. Gai
    - inhibits adenylyl cyclase
    - causes negative inotropy
  3. Gaq
    - activates phospholipase C
    - produces IP3 and DAG
    - stimulates release of ca from endoplasmic reticulum
    - smooth muscle contraction
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11
Q

Give some examples of processes that involve G protein coupled receptors?

A 
Vision
Taste
Smell
Behavioural and mood regulation 
Immune regulation (TLR responses)
Inflammation (histamine)
Autonomic nervous system (sympathetic and parasympathetic)
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12
Q

What G protein coupled receptor is found in the collecting ducts of the renal tubule, which is bound by ADH?

A

V2 Vasopressin receptor (V2R)

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13
Q

What condition results from an inactivating mutation of V2R?

A

Congenital diabetes insipidus

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14
Q

How does a tyrosine kinase linked receptor work?

A
  • Ligand binds to receptor
  • Receptor dimerizes, allowing tyrosine to be transphosphorylated by its partner receptor
  • This allows other proteins to ‘dock’ and become phosphorylated
  • This amplifies a signal through the membrane
  • The process is aided by relay proteins
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15
Q

Give some examples of tyrosine kinase linked receptors?

A

Epidermal growth factor receptor
Fibroblast growth factor receptor
Vascular endothelial growth factor

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16
Q

What is the link between EGFR and cancer?

A

EGFR is a member of the HER growth receptor family.
It is involved in growth, differentiation and survival.
Many tumours express EGFR.

EGFR involves STAT, AKT etc

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17
Q

Which tumours express EGFR?

A

Colorectal, head and neck, pancreatic, lung, breast, renal, glioblastoma

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18
Q

What therapies inhibit EGFR as a form of chemotherapy?

A

Monoclonal antibodies (trastuzamab aka herceptin in breast cancer)
Tyrosine kinase inhibitors (eg. imatinib in CML)
Antisense (prevents transcription)

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19
Q

How does an intracellular receptor work? What are the 3 domains involved?

A
  • Small/hydrophobic chemical messengers cross the membrane
  • Ligand activate the receptors (found in nucleus/cytosol)
  • Activated complex can act as a transcription factor, turning on specific genes

3 domains:

  • Ligand binding domain
  • DNA binding domain
  • Activation domain
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20
Q

What hormones often bind to intracellular receptors?

A 
Steroid hormones (eg. ENaC)
Thyroid hormones

They are both hydrophobic

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21
Q

What type of receptor do hydrocodone and lisinopril target?

A

G protein coupled receptor

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22
Q

What are the functions of endothelial cells?

A
  1. Autoregulation of tissue perfusion
  2. Facilitate exchange of blood gases, nutrients and waste
  3. Tissue repair and angiogenesis
  4. Homeostasis of blood coagulation
  5. Direct immune cells to their destination
23
Q

What junctions can endothelial cells be joined by?

A

Tight junctions
Gap junctions
Adherens junctions

24
Q

What is the role of tight junctions?

A

Form an impermeable barrier to hold cells together

25
Q

What is the role of gap junctions?

A

Facilitate communication

26
Q

What is the role of an adherens junction?

A

Provide anchorage and structure

27
Q

Which chemicals cause endothelial vasodilatation?

A

Nitric oxide
Prostaglandins
Bradykinin

28
Q

Which chemicals cause endothelial vasoconstriction?

A

Endothelin 1

Angiotensin II

29
Q

What are the four methods of transport across the endothelium?

A

Diffusion - concentration gradient
Filtration - pressure gradient
Vesicular - transcytosis
Active transport - against concentration gradient

30
Q

What are the 3 types of capillary endothelium?

A

Continuous - facilitates blood flow along the vessel, many tight junctions
Fenestrated -passage of small molecules through transcellular pores
Discontinuous - passage of large molecules for exchange, poorly structured basement membrane

31
Q

Where do you get continuous endothelium?

A

Skin
Muscle
Lung
CNS

32
Q

Where do you get fenestrated endothelium?

A

Exocrine
Glomeruli
Intestinal mucosa

33
Q

Where do you get discontinuous endothelium?

A

Liver
Spleen
Bone marrow

34
Q

Describe the endothelium of the BBB

A

Highly specialised, only allows small, lipid soluble molecules to pass via active transport

35
Q

Describe the endothelium of the liver

A

No basement membrane, very low pressure and leaky to allow waste exchange

36
Q

Describe the endothelium of the kidney

A

Fenestrated endothelium lines the glomeruli, acting as a second filter after the podocytes. Allows urea, sodium and rate to go through but not protein and cells

37
Q

Describe the process of angiogenesis

A
  1. CLONAL EXPANSION - division of mature endothelial cells
  2. Migration towards damaged tissue in response to growth receptors (VEGF - tyrosine kinase linked)
  3. Growth of new blood vessels
  4. Supplementation of oxygen and nutrients
38
Q

Describe the process of leukocyte extravasion (leakage). What molecules are involved in this process?

A

ADHERINS AND SELECTINS

  • They bind to oligosaccharides on the neutrophil, which slows the movement of it
  • Neutrophil expresses P-selectin and integrin, which binds ICAM-1
  • This causes the neutrophils to roll along the wall (margination)
  • Bonds become stronger and rolling slows
  • Neutrophils move through the endothelium to sites of infection (diapedesis)
  • Weakened bonds between endothelial cells allow other molecules and fluid to cross

The main site of this is in post capillary venues
NB this process is also involved in tumours

39
Q

What is margination?

A

When neutrophils roll along the surface of the endothelium in response to adherins and selection in inflammation

40
Q

What is diapedesis?

A

When neutrophils move through the endothelium to reach the site of infection, in response to adherins and selectin

41
Q

Which pro-inflammatory cytokines activate the endothelium, and how do these lead to sepsis?

A

IL1, IL6, TNFa

  • Trigger localised apoptosis and necrosis
  • Weaken junctions causing oedema
  • Increased vasodilation
  • Increased production of pro-thrombotic factors such as VWF
42
Q

What pro-atherosclerotic agents activate the endothelium, and what is the pathophysiology?

A

Lipids, glucose and smoking

  1. Increase cellular permeability to lipoprotein
  2. Increase production of extracellular matrix resulting in plaque formation
  3. Altered expression of cell surface receptors regulating anticoagulation and diapedesis
43
Q

How do endothelial cells counteract coagulation?

A

Production of anti platelets, fibrinolytic agents (antithrombin) and anticoagulants

44
Q

How does an endothelium become stimulated/activated in disease?

A
  1. Stimulation - e.g. from vWF release or P-selectin expression
  2. Activation - prolonged exposure to stimules, alters gene transcription
45
Q

What is the role of TNF?

A

Pro-inflammatory cytokine:

  • Activates macrophages and neutrophils
  • Stimulates T cell activation
  • Key mediator of response to gram negative septicaemia
  • Anti-tumour effect
46
Q

Name some TNF blockers. What are the side effects?

A

Infliximab, adalimumab - used in severe rheumatoid.

SE - reactivation of latent TB and demyelination

47
Q

What is VEGF-A?

A

Growth factor - acts on microvascular endothelial cells to initiate ‘vascular sprouting’

Secreted by macrophages in response to hypoxia due to disruption of blood supply.
Promotes chemotaxis in angiogenesis and tissue repair and is overexpressed in cancer.

48
Q

Where do foam cells usually accumulate in atherosclerosis?

A

Tunica intima

49
Q

Which structure is responsible for storage of vWF and P-selectin?

A

Weibel Palade body

50
Q

What is the pathophysiology of myasthenia gravis?

A

Autoimmune destruction of the nicotinic ACH receptor (ligand gated), so there is less depolarisation

51
Q

What are the symptoms of MG?

A

Fatiguability
Eyelid drooping
Slurring of speech

52
Q

How is MG investigated?

A
  • Ice test - leads to improvement of eyelid dropping
  • Anti-AchR autoantibodies
  • Edrophonium tests - blocks ACHase and improves symptoms
53
Q

How is MG treated?

A

Neostigmine - acetylcholinesterase inhibitor

54
Q

What is the AKT pathway?

A

G protein coupled pathway
IGF binds to G protein, activates PIP3 and the AKT pathway.

AKT up regulates many other pathways (eg. mTOR) and this can BLOCK APOPTOSIS (implication in cancer)

4TH YEAR - CSIM2 (20 decks)

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