PBL 0- Introductory lectures Flashcards
What are the mechanisms of Cell- cell communication?
Local Communication/short range
Direct
o Juxtacrine (membrane bound signal molecule
o Gap junctions- direct flow to neighbour
Through extracellular fluid
o Paracrine – local mediator
o Autocrine- receptor on the same cell
- Across synaptic clefts – very fast through post synaptic receptors
Long Range- Through circulatory system
- Neuroendocrine – neuron to a cell
- Endocrine- endocrine cell to a cell
What can neurotransmitters be made from? what are examples of these?
Amino acid derivatives
o Most of the water soluble hormones
o Thyroid hormones – lipid soluble
Peptide hormones
o Polypeptide and small proteins eg Insulin, growth hormones
o Glycoproteins eg TSH, EPO
Lipid derivatives
o Steroid hormones (from cholesterol) eg sex hormones
Eicosanoids (from
Lipid soluble hormones
Explain the following: Binding: Location of receptors: Synthesis: Storage: Release: Travel: Action: Examples:
Bind :
Most bind to intracellular receptors, however some will bind to surface receptors (eicosanoids)
Location of receptors:
Either in the cytosol or the nucleus
Synthesis :
Denovo in response to a stimulus
Storage:
No intracellular storage- therefore and increase in secretion = an increase synthesis
Release:
Slow diffusion across the plasma membrane- no specific mechanism
Travel:
Hydrophobic- reversibly attached to carrier proteins- tiny amount free in the blood
- Most bound to hormone specific carrier proteins
- Some bound to plasma albumin- non specific transporter
- Carrier proteins delay metabolism and protect against enzymatic degradation
Action:
- Free hormone enters by diffusion (passive or facilitated), binds to intracellular receptors
- Nuclear hormone receptor complex affects gene transcription
- Changes occur in synthesis of specific proteins
Eg : thyroid and steroid hormones
End result = slow, long term physiological changes
Water Soluble Hormones: Explain the following: Binding: Location of receptors: Synthesis: Storage: Release: Travel: Action: Examples:
Synthesis :
Pre made and packaged into vesicles
- from amino acids via enzymatic reaction ie classical NT ( Glutamate into GABA)
- Peptide/small protein hormones- as pre-pro-hormone or prohormone . mature hormone is released from precursor by proteolytic cleavage
Storage:
IN the cytoplasm until released
Transport:
Hydrophilic so once they are released they travel freely in the blood
Release : exocytosis in response to a stimulus
Bind :
Cell surface receptors
- Cannot penetrate cell membrane
- Triggers activation of intracellular signaling cascade
- Cell response- activation of inactive, preexisting, pre made proteins ensures quick response to hormonal action
EG:
- All peptide hormones – ie insulin
All amino acid derived hormones except Thyroid (this is lipid soluble)
What is phosphorylation and what carries this out?
Protein Kinase
- Enzyme that transfers phosphate group
- Most often phosphorylation leads to protein substrate ACTIVATION
Protein Phosphatase
- Enzymes that removes the phosphate
- Results in release of Pi
- INACTIVATES proteins
What does phosphorylation do?
- When activated kinases/phosphatases will bind to their substrate
- Phosphorylation can promote:
o Enzyme activation or inactivation (but mostly activation)
o Increase or decrease protein-protein interactions
o Changes in protein sub cellular localisation
Explain the Phosphorylation cascade
Typical phosphorylation cascade
Starts with unstimulated cell
- Typically intracellular proteins are inactive
Upon cell stimulation
- Receptor becomes activated by binding of signaling molecule
- Receptor activation leads to kinase activation through phosphorylation or activation by second messenger
- (typically protein phosphatases are inactivated)
- signaling cascade leads to substrate activation (through pohphorylation)
Termination of signaling
- typically phosphatases
Sequential cascade of activation transmits original signal
Most often activation
What are the types of Cell surface receptors
what is the genomic and non genomic response?
1) GPCR- adrenaline
2) Enzyme linked receptors- insulin
3) Ion channel-linked receptors
Specificity of hormonal action determined by specificity of extracellular receptor
The extracellular receptor will determine the specificity of intracellular signal generates.
Signalling cascade effects- (both occur)
- Slow
Long term effects occur slowly by activating cascade that regulate gene transcriptlion and protein synthesis “genomic response”
- Fast
Results in fast effects and rapid changes in cell behaviour “non genomic response”
How does a GPCR work?
GPCR- Largest family of surface receptors
- interacts with the G-Protein
- Ligand binding activates a G Protein which then activates an enzyme
- This generates a specific second messenger or modulates an ion channel
Allows for signal amplification
How does an ion channel receptor work?
- Ligand binding changes the conformation of the receptor so that specific ions can flow through it
- The resulting ion movements alter the electric potential across the cell membrane
- Eg ACH receptor at the nerve- muscle junction
What are second messengers?
- Short lived intracellular signaling molecules
- An elevated concentration leads to a rapid change in the activity in cellular enzymes
- Removal of a second messenger can end the cellular response
- Examples include:
o cAMP cGMP
o Calcium
o Membrane derived lipids- Inositol
o Gas- NO
What are enzyme linked receptors?
Two types
- Receptors with intrinsic enzymatic activity
o Intrinsic catalytic activity in cytosolic domain activated by binding of a ligan
o Majority are receptor protein kinases eg Insulin
- Tyrosine kinase linked receptors
o Ligand binding causes receptor activation, triggering the binding and activation of cytosol protein tyrosine kinases
This turns phosphorylates
How is Hormonal signalling terminated?
Targets:
Ligand removal
o Rapidly fall of the receptor, removed from the circulation or degraded
Receptor level
o Inactivation – by dephosphorylation, binding of inhibitory protein
o Internalization – endocytosis and lysosomal digestion
o Desensitization- receptor no longer responds to the signal (insulin resistance)
Relay molecules, enzymes and substrates
o Inactivation: often by dephosphorylation by protein phosphatases
o Degradation: second messenger cAMP is degraded by phosphodiesterase
o Removal: second messenger calcium is pumped out of the cell
Importance:
Persistent activation is bad. Need to inactivate for homeostasis
What are the main types of Neurotransmitters?
Which ones are considered the “classic” neurotransmitters?
Amino acids - GABA - Glutamate - Glycine Amines - Acetylcholine - Dopamine and Serotonin - Adrenaline and noradrenaline - Histamines Peptides: - CCk, ENk, Substance P Classic Neurotransmitters are the small ones
How is the effect of hormones regulated?
Response to hormones depends on amount of hormone as well as cell sensitivity. This is regulated :
Levels of hormones
o Rate of hormone synthesis/secretion
o Rate of hormone delivery to target
o Rate of clearance of hormone (excretion, degradation)
o Negative or positive feedback loops that result in increase or decrease hormone production and release
Cellular sensitivity to hormones:
Increase in number and/or sensitivity of receptors to hormone ligand
How are Neurotransmitters synthesized?
Small molecules: Amino acids and Amines
- Synthesized from precursors by enzymatic reaction
- Packaged into small synaptic vescicles
- All steps for synthesis occur in the presynaptic nerve terminal
Neuropeptide hormones
- Made from large precursors
- synthesized in the cell body ( Rough ER)
- Packaged into large secretory granules (packaged by Golgi apparatus)
- Transported to terminal
Are slower to release than the amino acid and amine transporters
