Lecture 6: Receptors and Signal Transduction Mechanisms Flashcards Preview

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1

Endocrine signaling

Long distance communication. A hormone carried to the blood to a distinct target cell where it has effect.

2

Paracrine signalling

A secretory cell releases signalling molecules to an adjacent target cell, activating receptors on this cell. Could be across a synapse. Must have a neighbour for this type of signalling

3

Autocrine signalling

A cell releases a signalling ligand that feeds back to the cell that released it and binds to receptors.

4

Signalling by plasma membrane attached proteins

The ligand is attached to one cell and binds to a receptor on an adjacent cell. The cells are conjoined by this arrangement.

5

For a drug to have selective action on a cell it muster interact with:

A discrete target (receptor) on that cell

6

Receptors (what they are made of, where they are located)

Made of protein
Typically at the cell surface but also nuclear membrane proteins and even enzymes can act as receptors.

7

Binding of drugs to receptors results in (3):

-Conformational changes in receptor.
-Transduction of the signal via alterations in cytosolic metabolism
-Changes in cell function and gene transcription

8

Orthosteric site

Where endogenous ligands bind a receptor. Most drugs mimic endogenous ligands, so they will also bind here. The receptor site that binds the neurotransmitter.

9

Allosteric site

A distinct site on a receptor that the endogenous ligand doesn't bind to. Can cause a change in the orthosteric site.

10

Ligand

Any endogenous neurotransmitter. Something that is recognized by and binds to a receptor.

11

The 5 ways in which drugs can intervene in neuronal receptor signalling (neuronal modulation)

1. Synthesis of transmitter in presynaptic nerve terminal
2. Release of transmitter and transport to the target cell
3. Detection of the signal by a specific receptor protein
4. Change in cellular metabolism triggered by the receptor signalling molecule complex
5. Removal of the signal, terminating the cellular response.

12

Receptor types

-Ligand gated ion channel (LGIC)
-GPCR
-Receptor tyrosine kinases (RTK)
-Nuclear receptors

13

Another term for LGIC

Ionotropic receptors

14

LGICs

-Present on cell membrane
-Composed of 3-5 subunits and a central aqueous channel
-Central pore requires binding of a ligand to change the conformation of the channel so that ions can pass through.
-Involved in fast neurotransmission.
-If the charge across the membrane is a favourable gradient, the ions will flow. NOT Voltage gated

15

Things that pass through LGICs

Na+, Ca2+, Cl-

16

Examples of LGICs

-Nicotinic ACh (non-selective for sodium and calcium)
-GABAᴬ: Inhibitory
-5-HT₃:

17

How do LGIC and voltage gated ion channels differ?

While LGIC need favourable membrane potential for ions to flow through, they are gated by the binding of a ligand. VGICs don't need this.

18

Nicotinic Receptor Signalling

-ACh is released and binds to its receptor
-Receptor is able to pass sodium ions into the cell with the gradient
-Small depolarizations in the muscle sum and cause action potentials and the muscle contracts.

19

Acetylcholine Esterase

-Membrane bound enzyme
-Hydrolyzes released ACh, producing choline and acetate that are recycled.

20

Where are LGICs that respond to ACh normally found?

-Nerve synapses at neuromuscular junctions.

21

Most drugs are targeted toward

GPCRs (at least 50%)

22

GPCR Superfamily

-Family A: Rhodopsin-like
-Family B: Glucagon/ VIP/Calcitonin
-Family C: Metabotropic glutamate and chemosensor

23

GPCR features

-7 transmembrane domains
-N terminal that is frequently extracellular
-Intracellular carboxy terminal

24

Function of IL3 loop

Slightly longer than others; has a function in binding downstream signalling molecules i.e. G-proteins

25

C-terminus

Important in decreasing association of the receptor with the G-protein

26

The G protein is inactive when bound to

GDP

27

When an agonist that stabilizes the signalling form of the receptor binds, it allows:

Association with the G protein and the removal of GDP, so that it can bind GTP. The heterotrimeric g protein breaks apart, and the G-alpha subunit will signal downstream proteins.

28

Effectors commonly associated with GPCRs (5)

-Adenylyl cyclase
-Phospholipases C & A2
-cGMP Phosphodiesterase
-Potassium channels
-Calcium channels

29

Orphan receptors and ligands

Things we see in research but haven't been able to put them into a class because we dont know how they function.

30

Steps of GPCR activation

-Ligand binds orthosteric binding site. GDP is exchanged for GTP and the G protein associates with the receptor.
-Dissociation of the heterotrimeric G protein. alpha-GTP goes to effector and activates it
-Activation of effector is stopped when the alpha subunit hydrolyzes GTP. The heterotrimeric subunits come back together.