Signal Transduction 2

How are signal transduction pathways grouped

By the type of receptor.

What are the 4 major types of membrane-bound receptors

• Ion channel-enclosing receptors

• 7-transmembrane domain (7-TM) receptors

• 1 hydrophobic domain receptors with enzyme activity

• 1 hydrophobic domain receptors without enzyme activity

Besides membrane-bound receptors, what other receptor classes exist

Cytosolic receptors

Nuclear receptors

What is an example of an ion channel-enclosing receptor

The nicotinic acetylcholine receptor (nAChR)

True/False Nicotinic acetylcholine receptors are only expressed in excitable cell types

False: Expressed in a variety of excitable and non-excitable cell types

What types of cells express the nicotinic acetylcholine receptor?

Skeletal muscle cells (neuromuscular junction)

Neurons

Adrenal medulla chromaffin cells (Acetylcholine (Ach)-induced epinephrin release)

What is the sequence of events in acetylcholine signalling at the neuromuscular junction?

Impulse → Ca²⁺ influx → ACh release → Na⁺ depolarization → Action potential → SR Ca²⁺ release → Contraction

How is the signal switched off at the neuromuscular junction?

1. Degradation of acetylcholine by acetylcholinesterase in the synaptic cleft (within milliseconds).

2. Receptor desensitisation by phosphorylation and internalisation.

Receptor: Nicotinic acetylcholine receptor.

Amplification system: Ion fluxes (Na⁺ depolarization, Ca²⁺ release).

Acceptors: Muscle contractile machinery.

Biological response: Skeletal muscle contraction.

What does nicotine do at the nicotinic receptor?

Nicotine activates the receptor, mimicking acetylcholine, leading to stimulation.

Why is nicotine addictive?

Because it stimulates nicotinic receptors in neurons, causing dopamine release

Give an example of a 7-transmembrane domain receptor

β adrenergic receptor

Describe the structure of a 7-TM receptor

Seven transmembrane domains with the N terminus (amino terminal) outside the cell & the C terminus (carboxyl terminal) in the cytosol inside the cell.

The ligand sits in a pocket formed by transmembrane helices

How do 7-TM receptors interact with G proteins?

Upon activation, they bind G proteins via the 3rd transmembrane domain.

(aka G protein-coupled receptor)

Where (specific structure) & by what (cells) does epinephrine get produced

Chromaffin cells in the adrenal medulla

Effects of epinephrine on body systems

What happens when epinephrine reaches a muscle cell

To which protein superfamily do G proteins belong?

The GTPase protein superfamily (with over 50 members)

Explain the amplification system of G protein-activated adenylate cyclase

1 occupied receptor → Many subunits being activated (amplification)

PKA phosphorylates many cellular proteins which cause the cellular response (amplification)

We have gone through the amplification system. Now, what are the receptors & what regulates them

Protein kinase A (PKA) regulates the acceptors:

• Enzymes

• Structural proteins - troponin, myosin light chain kinase

• Ion channels - IP3-sensitive calcium channel

• Transcription factors (cAMP response element (CRE) binding protein (CREB)

Cystic Fibrosis is an underactive/nonfunctional CFTR (cystic fibrosis transmembrane conductance regulator). What would an overactive CFTR be

Cholera

How does Cholera cause an overactive CFTR

1. Cholera toxin ADP-ribosylates → freezes Ga in active conformation → constitutive adenylate cyclase activity & high cAMP

3. cAMP drives protein kinase A activity

4. PKA phosphorylates & activates CFTR (cystic fibrosis transmembrane conductance regulator) Cl⁻ channels on the apical membrane.

Moving onto the next amplification system…

:)

Phospholipase C can be activated via what

G proteins

or

Tyr phosphorylation

What happens when phospholipase C is activated

It cleaves (hydrolyses) PI(4,5)P₂ (Phosphatidylinositol 4,5-bisphosphate) into membrane bound diacyl-glycerol and cytosolic inositol 1,4,5-trisphosphate (IP₃)

Fate of membrane bound diacyl-glycerol and cytosolic inositol 1,4,5-trisphosphate (IP3)

Diacylglycerol activates protein kinase C (PKC)

Inositol 1,4,5-trisphosphate (IP3) releases Ca2+ from the endoplasmic reticulum and fully activates protein kinase C (PKC) with Diacylglycerol.

IP3 can’t activate PKC by itself, but Diacylglycerol can.

What types of receptor is The Inositol 3-phosphate receptor

Intracellular, ion channel-enclosing receptor

what ion is associated with The Inositol 3-phosphate receptor

Ca2+

Briefly how does The Inositol 3-phosphate receptor work

The inositol 1,4,5-trisphosphate (IP₃) receptor is a ligand-gated Ca²⁺ channel on the endoplasmic reticulum (ER) membrane.

When IP₃ binds, the receptor opens → Ca²⁺ ions flow out of the ER into the cytosol

Calcium activates protein by 2 mechanisms - what are they

Direct binding

or

Binding to a calcium-activated regulatory subunit

What calcium targets are directly activated by Ca2+

Name some calcium sensing regulatory subunits

What are the targets of protein kinase C

Name some PLC-induced biological responses