ligand gated ion channels and G-protein coupled receptors

receptor

a molecule that recognises specifically small molecules whose binding brings about the regulation of a cellular process

Ligand-gated ion channels (ionotropic receptors)

They form a channel between the extracellular and intracellular environment of the cell/organelle. The channel is made up of subunits which can vary

Cellular change occurs in milliseconds

How do ligand-gated ion channels alter cellular function?

Ligand has to bind to the channel causing conformational change so then the ion can pass through via the electrochemical gradient. This occurs in milliseconds.

How does this alter cellular function?

Activate signalling pathways and alter the excitability of a cell

Role of ligand gated ion channels in depolarisation

They are responsible for that initial depolarisation event which causes the release of neurotransmitter

What is depolarisation and how does it work?

This occurs in excitatory ligand-gated ion channel e.g. Acetylcholine receptor

A ligand binds to its ligand-gated ion channel - causes a flow of positive ions to go inside the cell.

The inside of cell becomes more positive compared to outside (depolarisation) which results in a voltage change and triggers the voltage-gated ion channels to open. (Na+ moves into the cell)

So the action potential moves along.

What is hyperpolarisation and how does it work?

This occurs in inhibitory ligand-gated ion channels e.g. GABA receptor

A ligand binds to its ligand-gated ion channel - causes a flow of negative ions to go inside the cell.

The inside of cell becomes more negative compared to outside (hyperpolarisation) - this means no activation of voltage-gated sodium channels so no action potential is generated.

Examples of LGICs

Nicotinic acetylcholine and GABA A receptors

What is the neuromuscular junction?

Allows for communication between nervous system and skeletal muscle to initiate contraction

Motor nerves from spinal cord synapse with skeletal muscle fibres

Each branch form an end plate region on a single muscle fibre as the motor end plate

neurotransmitter = acetylcholine (ACh) receptor = nAChR (nicotinic acetylcholine receptor)

How does the neuromuscular junction work?

Acetylcholine binds to nicotinic acetylcholine receptor - causes Na+ to move inside the cell which results in depolarisation of the skeletal muscle cell

This drives a voltage change - triggers influx of Na+ via voltage gate channels into the skeletal muscle cell which results in an action potential

This triggers an increase second messenger which is Ca2+ in this case

This causes muscle contraction

What is a neuromuscular blocking agent (NMB)?

Acts as an antagonist ( has affinity for a receptor but no intrinsic activity, which prevents the receptor from being activated by the endogenous agonist)

Prevents acetylcholine from binding to receptors so muscle contraction cannot occur - paralysed the muscle

Use of NMBs

Tracheal intubation - ventilation of lungs allows delivery of O2 and removal of CO2 by protection against aspiration of gastric contents.

The larynx is a muscle (what tracheal intubation passes through) - NMBs can be used to relax the larynx and allow easy passage of the intubation tube into the trachea

Can also be used for surgical procedures specifically to cause relaxation of abdominal muscles as they can prevent tearing

Also can be used for therapeutic hypothermia - reduce body temperature to 32-34 degrees as it can improve neurological recovery if the patient has suffered from a stroke - the NMBs prevent shivering and should only be taken once patient is anesthetized.

What are G protein-coupled receptors compromised of?

7 transmembrane domains, extracellular N terminus, intracellular C terminus

They are coupled to a G protein which has a trimeric structure - Gα, beta and gamma subunits

Cellular change occurs in seconds

How do G protein-coupled receptors work?

Agonist binds to one of the extracellular N-terminus which causes it to be activated. This stimulates the g-protein and the Gα separates from the beta and gamma subunits. It moves along the membrane, altering the effector molecule's basal activity, activating or inhibiting the effector molecule. This triggers a cellular response.

What are the Gα subunits and their role?

Gαs, Gαi, Gaq, Gα12 - this determines where the receptor inhibits or activates

Binds GDP/GTP and has GTPase activity

Effector molecule for Gαs?

adenylyl cyclase - when increased stimulation it increases cAMP

Effector molecule for Gαi?

adenylyl cyclase - when increased stimulation it decreases cAMP

Effector molecule for Gαq?

phospholipase C - when stimulated it increases DAG and IP3

What are the G beta and gamma subunit

There are 5 beta and 12 gamma which can form unique beta and gamma combinations - the effectors are usually ion channels, enzymes, and kinases

Smooth muscle and α1-adrenoreceptors

Arteries and arterioles contain a circular layer of smooth muscle - constriction of SM reduces the blood vessel diameter whilst relaxation of SM increases the diameter

Change in diameter of blood vessel has a large impact on blood pressure

Tone of SM controlled by: circulating humoral factors, sympathetic and parasympathetic nervous system, paracrine factors

α1-adrenoreceptors antagonists

antagonist binds to α1-adrenoreceptors on vascular smooth muscle cell

this blocks adrenaline (released from adrenal medulla due to stress) from binding to the receptors

This inhibits the G alpha Q subunit from activating phospholipase C which means IP3/DAG is not activated so Ca2+ will not be released

This results in relaxation of smooth muscle

Uses of α1-adrenoreceptors antagonists

Pheochromocytoma - tumor of the adrenal gland, secretes huge amount of adrenaline/noradrenaline, doxazosin (antagonist) reduces BP before and during surgery

Benign prostatic hyperplasia - urinary retention due to urethral obstruction, SM relaxtion of urethra, reduces urethral resistance, improves urine flow

Examples of G-protein coupled receptors

Dopamine and muscarinic acetylcholine receptors