V Cell Signalling

Cell Surface Receptors

Overview

Learning objective: Familiarise with major families of cell surface receptors.
Three main types:
- Ion channel linked receptors.
- Enzyme linked receptors.
- G protein linked receptors.
These receptors mediate responses to lipophobic messengers (water-soluble, cannot cross the cell membrane).

Cell Signalling Mechanism

Messenger released by source and binds to receptor.
Binding leads to cell response.
Signal transduction: Process of producing a response; aims to amplify the signal.

Receptor Types

Intracellular receptors (Lecture 4): For lipophilic messengers, located in cytosol or nucleus.
Cell surface receptors: For lipophobic messengers.
- Ion channel coupled receptors.
- G protein coupled receptors.
- Enzyme coupled receptors.

Phosphorylation

Changes in phosphorylation states of proteins are a common response to activated cell surface receptors.
Phosphorylation: Post-translational modification by kinases.
Dephosphorylation: Removal of phosphate by phosphatases.
Kinases and phosphatases regulate phosphorylation state.
Proteins are mainly phosphorylated on serine, threonine, and tyrosine residues.
Phosphorylation alters protein activity, often causing conformational change.
It's a reversible control mechanism ideal for signalling pathways.

Phosphorylation as a Molecular Switch

Acts as a switch between active and inactive forms of proteins.
Important to avoid futile cycles (simultaneous production and breakdown of compounds).
Futile cycles are wasteful.
Enzymes involved in synthesis or degradation are regulated by phosphorylation/dephosphorylation.
Example: One enzyme active for synthesis, another for degradation; phosphorylation regulates their activity.

Generalised Structure of Cell Surface Receptors

Integral membrane proteins with three basic domains:
- Ligand-binding domain (extracellular).
- Transmembrane domain (anchors receptor).
- Cytoplasmic domain (intracellular effector region).
Examples given: Epidermal growth factor receptor, insulin receptor, beta adrenergic receptors.

Domains

Ligand-binding domain: Extracellular, binds the ligand.
Transmembrane domain: Anchors the receptor to the membrane.
Cytoplasmic domain: Intracellular, effector region; relays the signal upon ligand binding.

Ligands for Cell Surface Receptors

Lipophobic messengers (water-soluble, not lipid-soluble).
Receptors are on the plasma membrane; ligand-binding domain faces extracellular fluid.
Transport in blood is not an issue due to water solubility.
Activation leads to changes in ion movement or phosphorylation of enzymes/key proteins
Contrast to intracellular receptors, which change gene expression.

Major Classes of Cell Surface Receptors

Ion channel linked receptors.
G protein linked receptors.
Enzyme linked receptors.

Ion Channel Linked Receptors

Ligand binding opens or closes ion channels.
Receptor and channel are the same protein.
Also called ligand-gated channels or transmitter-gated ion channels.
Plasma membrane's ion permeability determined by these channels.
Channels are specific to particular ions.

Types of Ion Channel Linked Receptors

Fast channels: Receptor and channel are the same protein; action is immediate.
Slow channels: Receptor and channel are separate proteins, linked by G proteins; action is slower because there is an intermediate between the receptor and the channel

Fast Ligand Gated Channels

Involved in detection of neurotransmitters.
Function as both receptors and ion channels.
Ligand binding changes ion permeability of the plasma membrane.
Action is direct and transient.
Involved in rapid synaptic signalling.
Binding changes receptor conformation, leading to opening or closing of ion channel.

Effects of Ion Movement

Changes electrical properties of target cells.
Ions can interact with proteins inside the cell.
Examples: Muscle contraction, hormone secretion, changes in metabolism.
Calcium channels: Influx of calcium can trigger various responses.

Mechanism of Action of Fast Ligand Gated Channels

Messenger binds to receptor, opening the ion channel.
Ions (sodium, potassium, chloride) move in or out of the cell.
Ion movement changes electrical properties, causing a response.
Example: Acetylcholine binding changes sodium and potassium permeability, altering cell excitability.

Structure of Ion Channels

Receptors are a family of related proteins with multiple polypeptide chains (alpha, beta, delta, gamma).
Encoded by different genes with high homology.
Arranged in a ring-like fashion in the membrane.
Polypeptides act as ligand-binding domains and regulatory domains.

Ion Channels as Drug Targets

Target for drugs like barbiturates (used for insomnia, depression, anxiety).
Implicated in diseases like schizophrenia, Parkinson's, epilepsy, and autism.

Enzyme Linked Receptors

Most are associated with tyrosine kinases (phosphorylate proteins on tyrosine residues).
Two types:
- Receptor tyrosine kinases: Receptor itself has intrinsic kinase activity.
- Tyrosine kinase associated receptors: Receptor associates with a separate tyrosine kinase.
Examples: Insulin signaling and growth hormone signaling.

Enzyme Linked Receptors Structure and Function

Transmembrane proteins with ligand-binding site outside and enzyme/effector inside.
Ligand binding activates the receptor and its enzyme.
Action is direct: changes phosphorylation state of signalling molecules on tyrosine residues.
Initiates signalling pathways involving phosphorylation on serine and threonine.

Enzyme Linked Receptor Types: Detailed Mechanism

Receptor and enzyme are the same protein: Inactive until ligand binds, causing dimerisation and activation of kinase domain. Kinase phosphorylates tyrosine residues, creating docking sites for signalling molecules.
Receptor associated with kinase: Ligand binding activates the receptor, which activates the associated kinase. Kinase phosphorylates signalling molecules, promoting a response.

Signal Transduction Mechanism for Tyrosine Kinase Receptors

Inactive tyrosine kinase domain in the absence of messenger.
Messenger binding activates tyrosine kinase, which phosphorylates proteins on tyrosine residues using ATP.
Phosphorylated tyrosine residues become docking sites for other proteins.
Alters metabolism, regulates protein synthesis, or changes gene expression.

G Protein Coupled Receptors

Linked to G proteins (GTP-binding proteins).
Activation leads to activation of G protein, which conveys the message to the next component.
Effectors are either ion channels or amplifier enzymes.
Amplifier enzymes generate second messenger systems.

Mechanism of Action for G Protein Linked Receptors (Slow Ligand Gated Channels)

Messenger binds to receptor, activating G protein.
G protein activates an ion channel.
Trimeric G protein (alpha, beta, gamma subunits).
Inactive G protein bound to GDP. Ligand binding causes GDP to be replaced by GTP, activating G protein and dissociating the alpha subunit.
Alpha subunit activates ion channel.

G Protein Receptors Associated with Enzymes

Effector is an amplifier enzyme.
Example: Adenylyl cyclase (synthesizes cyclic AMP from ATP).
Cyclic AMP (cAMP) is a second messenger involved in many biological processes.

Cyclic AMP Pathway

Messenger binds to G protein-linked receptor.
Activated G protein activates adenylyl cyclase.
Adenylyl cyclase synthesizes cAMP from ATP.
cAMP activates cyclic AMP-dependent protein kinase (protein kinase A).
Protein kinase A phosphorylates other proteins on serine and threonine residues, leading to a response.

Simplified Overview of Receptors

Intracellular receptors: Messenger crosses cell membrane.
Enzyme linked receptors: Change phosphorylation state of enzymes/proteins.
G protein linked receptors: Change ion movement or phosphorylation.
Ion channel linked receptors: Change ion movement.

Summary

Three types of cell surface receptors:
- Ion channel linked receptors: Change ion movement.
- G protein linked receptors: Change ion movement or phosphorylation.
- Enzyme linked receptors: Change phosphorylation of key enzymes/proteins.