WEEK 11: RECEPTOR TYPES

Ion Channel Receptors

• Receptor protein is part of an ion channel protein complex

• Receptor binds a messenger leading to an induced fit

• Ion channel is opened or closed

• Ion channels are specific for specific ions (Na+, Ca2+, Cl-, K+)

• Ions flow across cell membrane down concentration gradient

• Polarises or depolarises nerve membranes

• Activates or deactivates enzyme-catalysed reactions within cell

General principles

• Receptor protein is part of an ion channel protein complex

• Receptor binds a messenger leading to an induced fit

• Ion channel is opened or closed

• Ion channels are specific for specific ions (Na+ , Ca2+, Cl- , K+ )

• Ions flow across cell membrane down concentration gradient

• Polarises or depolarises nerve membrane

-polarised: inside of cell –ve charged compared with the outside

-crucial for the cell’s ability to generate and transmit signals a.k.a action potentials

• Activates or deactivates enzyme-catalysed reactions within cell

Structure: Nicotinic receptor

• Made up of 5 subunits of 4 different types

• Binding occurs mostly on the alpha subunits

• Small amount of binding interaction on other subunits

Structure: Glycine receptor

• Made up of 5 subunits of 2 different types

• Binding occurs on the alpha subunits

• No binding interaction on other subunits

Detailed structure

Gating

• Fast response measured in msec

• Ideal for transmission between nerves

• Binding of messenger leads directly to ion flows across cell membrane

• Ion flow = secondary effect (signal transduction)

• Ion concentration within cell alters

• Leads to variation in cell chemistry

• Messenger binds to receptor binding site

• Induced fit results in further conformational changes

• TM2 segments rotate to open central pore

G-protein coupled receptors

• Receptor binds a messenger leading to an induced fit

• Opens a binding site for a signal protein (G-protein)

• G-Protein binds, is destabilised then split

• G-Protein subunit activates membrane bound enzyme

• Binds to allosteric binding site

• a specific location on a protein e.g. enzyme or receptor, that’s distinct from the main binding site

• Induced fit results in opening of active site

• Intracellular reaction catalysed

Ligands

• A molecule or ion that binds to another molecule (often a metal ion or a protein receptor) to form a complex

• Monoamines

e.g. dopamine, histamine, noradrenaline, acetylcholine

• Nucleotides

• Lipids

• Hormones

• Glutamate

• Ca2+

G-protein receptor sub-types

Receptor types and subtypes

Tyrosine Kinase Linked Receptors

• Bi-functional receptor / enzyme

• Activated by hormones

• Overexpression can result in cancer

Tyrosine kinase linked receptors: general principles

 • Protein serves dual role - receptor plus enzyme

• Receptor binds messenger leading to an induced fit

• Protein changes shape and opens intracellular active site

• Reaction catalysed within cell

• Overexpression related to several cancers

Structure

Tyrosine kinase

Tyrosine Kinase phosphorylates the phenol group of tyrosine

Epidermal growth factor receptor (EGF- R)

• Dimerisation of receptor is crucial

• Phosphorylated regions act as binding sites for further proteins and enzymes

• Results in activation of signalling proteins and enzymes

• Message carried into cell

Insulin receptor (tetrameric complex)

Growth hormone receptor (GH)

Intracellular receptors (aka nuclear receptors)

• Chemical messengers must cross cell membrane

• Chemical messengers must be hydrophobic

• Example - steroids and steroid receptors

Mechanisms

1. Messenger crosses membrane

2. Binds to receptor

3. Receptor dimerisation

4. Binds co-activator protein

5. Complex binds to DNA

6. Transcription switched on or off

7. Protein synthesis activated or inhibited

Oestrogen Receptor is intracellular

Helix 12 (H12): crucial structural element withing the ligand-binding domain that plays a key role in determining whether the receptor acts as an agonist (activates gene transcription) or antagonist (inhibits gene transcription)

AF-2: involved in recruiting coactivator complexes that interact with the DNA and enhance gene expression

Signal transduction

G-proteins

Signal transduction involving G-proteins

Signal transduction involving G-proteins

Glycogen Metabolism - triggered by adrenaline in liver cells

Coordinated effect: activation of glycogen metabolism inhibition of glycogen synthesis

Adrenaline has different effects on different cells:

e.g. activates fat metabolism in fat cells

Three major types of G proteins exist:

i.e. Gs , Gi and Gq

These activate different effectors and start different signal pathways

Drugs interacting with cyclic AMP signal transduction

Cholera toxin causes constant activation of cyclic AMP leading to diarrhoea

Theophylline and caffeine inhibit phosphodiesterases

- phosphodiesterases responsible for metabolising cAMP

- cAMP activity prolonged

Phosphorylation reactions

• Prevalent in activation and deactivation of enzymes

• Phosphorylation radically alters intramolecular binding

• Results in altered conformations

Desensitization and sensitization

• Receptors become desensitized on long term exposure to agonists

• Receptors become sensitized on long term exposure to antagonists

Desensitization

• Receptors become desensitized on long term exposure to agonists

• Prolonged binding of agonist leads to phosphorylation of receptor

• Phosphorylated receptor changes shape and is inactivated

• Dephosphorylation occurs once agonist departs
 

Sensitization

• Receptors become sensitized on long term exposure to antagonists

• Cell synthesises more receptors to compensate for blocked receptors

• Cells become more sensitive to natural messenger

• Can result in tolerance and dependence

• Increased doses of antagonist are required to achieve same effect (tolerance)

• Cells are supersensitive to normal neurotransmitter

• Causes withdrawal symptoms when antagonist withdrawn

• Leads to dependence