Lecture 5 - Synapses and Chemical Neurotransmission

Where is the neurotransmitter synthesised and stored in a neuron?

In the neuron and stored in vesicles in the presynaptic terminal

What event initiates neurotransmitter release at the synapse?

An action potential invades the presynaptic terminal

What does depolarisation of the presynaptic terminal cause?

It causes the opening of voltage-gated Ca²⁺ channels

What happens after voltage-gated Ca²⁺ channels open?

Ca²⁺ flows into the presynaptic terminal

How does Ca²⁺ trigger neurotransmitter release?

Ca²⁺ causes vesicles to fuse with the presynaptic membrane

How is the neurotransmitter released into the synaptic cleft?

Via exocytosis from the fused vesicles

Once released, where does the neurotransmitter go?

It binds to receptor molecules in the postsynaptic membrane

What happens when neurotransmitters bind to postsynaptic receptors?

Postsynaptic channels open or close

What is the effect of postsynaptic channel opening or closing?

It generates a postsynaptic current, causing an excitatory or inhibitory postsynaptic potential that changes the cell's excitability

What happens to the vesicle membrane after neurotransmitter release?

It is retrieved from the plasma membrane for reuse

What do voltage-gated Na⁺ and K⁺ channels do?

They conduct nerve impulses down the axon of a neurone

What is the role of ligand-gated channels, e.g., acetylcholine receptors?

They communicate nerve impulses between different neurones

What is the function of gap junctions in neurones?

They are important for synchronising signals and transferring nutritional metabolites

How is a Na⁺ channel structured?

It has four subunits fused into one polypeptide

How is a K⁺ channel structured?

It has four separate subunits that come together

What is the ball and chain model related to?

Signal inactivation of voltage-gated ion channels

What is the inactivation domain in the ball and chain model?

A “ball” attached to the channel by a flexible chain

What happens when the channel depolarises?

The channel opens and a negatively charged binding site is created for the positively charged ball

How does the ball inactivate the channel?

The ball moves into the binding site and blocks the channel, stopping ion flow

What is the structure of an acetylcholine ligand-gated channel receptor?

It is a pentamer (made of five subunits)

What happens when a ligand binds to a ligand-gated channel receptor?

It causes a structural change that allows the pore to open

Give examples of ligand-gated ion channels activated by extracellular neurotransmitters

Channels activated by glutamate and acetylcholine

How can ligand-gated channels be activated intracellularly?

By second messengers such as Ca²⁺, cAMP, or cGMP

What factors cause gap junctions to close?

Low calcium, low pH, changes in membrane potentials, and phosphorylation

How long are gap junctions typically open once formed?

For seconds to minutes

What is the main function of gap junctions?

They link the cytosol of one cell to another

What can move across gap junctions?

Inorganic molecules and small ions

Give examples of events where gap junctions help synchronise activity.

Heart pumping and labour contractions

How many distinct molecular mechanisms do cell surface receptors use to receive signals?

Four

What are the four types of cell surface receptors?

1) Ligand-gated ion channels
2) Receptors with intrinsic guanylyl cyclase activity
3) Receptors with intrinsic or associated tyrosine kinase activity
4) G-protein-coupled receptors (GPCRs)

What are G-protein-coupled receptors linked to?

Opening/closing of ion channels, modulation of adenylyl cyclase, and phosphoinositide-specific phospholipase C activities

What are neurotransmitters?

Chemicals transferred across a neuronal synapse to either promote or inhibit a signal

Give an example of a small molecule neurotransmitter

Acetylcholine

Name some amino acid neurotransmitters

Glutamate, aspartate, GABA, glycine

Give an example of a purine neurotransmitter

ATP

What are biogenic amines?

Neurotransmitters derived from amino acids, including catecholamines, indoleamine, and imidazoleamine

Which neurotransmitters are catecholamines?

Dopamine, adrenaline, noradrenaline

Which neurotransmitter is an indoleamine?

Serotonin

Which neurotransmitter is an imidazoleamine?

Histamine

Give examples of peptide neurotransmitters

Methionine enkephalin and Substance P

What is the amino acid sequence of Substance P?

Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met

What is the structure of acetylcholine?

What type of neurotransmitter is acetylcholine?

Predominantly excitatory, especially at skeletal muscles, but can be excitatory or inhibitory at other sites in the CNS and PNS

Where do cholinergic pathways typically begin and end?

They begin in the basal forebrain complex (BFC) and end in the PNS

What is acetylcholine’s role in the cortex?

It is important for cortical stimulation, including regulation of sleep

How many types of acetylcholine receptors are there?

Two

What type of receptor is a nicotinic acetylcholine receptor?

A ligand-gated ion channel that gives a fast response

What type of receptor is a muscarinic acetylcholine receptor?

A G-protein-coupled (metabotropic) receptor that acts much slower

Where are nicotinic receptors located?

Most parasympathetic targets and all autonomic ganglion cells

What is the response of nicotinic receptors?

Relatively fast postsynaptic response

Where are M1 receptors located?

Smooth muscle and glands of the gut

What is the response of M1 receptors?

• Smooth muscle contraction

• Increased glandular secretion

• Relatively slow response

Where are M2 receptors located?

Smooth and cardiac muscle of the cardiovascular system

What is the response of M2 receptors?

Smooth muscle contraction and inotropic effect on cardiac muscle

Where are M3 receptors located?

Smooth muscles and glands of all targets

What is the response of M2 receptors?

Smooth muscle contraction and glandular secretion

What is the structure of adrenaline?

What is the structure of noradrenaline?

What is the structure of dopamine?

What are catecholamines?

Neurotransmitters that contain a catechol group (benzene ring with two hydroxyl groups) and an amine group

Which nervous system do catecholamines mainly affect?

The sympathetic nervous system

Which neurons synthesise catecholamines?

Adrenergic neurones

What amino acid are catecholamines derived from?

Tyrosine

Why is tyrosine hydroxylase (TH) important?

It is the rate-limiting enzyme in the synthesis of all catecholamine

What happens if tyrosine hydroxylase is absent in embryos?

Incompatible with life

What are examples of catecholamines?

Adrenaline, noradrenaline and dopamine

Where is dopamine mainly located?

Mainly in the brain, with a few peripheral locations

Is dopamine excitatory or inhibitory?

Primarily an excitatory neurotransmitter

What transporter is unique to dopaminergic neurons?

Dopamine transporter (DAT)

Where do major dopaminergic neuron circuits originate?

The substantia nigra

What are the key functions of dopamine?

Motivation and reward, memory, and voluntary movement

How many types of dopamine receptors are there?

D1a, D1b, D2, D3, D4

What intracellular signalling pathway do dopamine receptors use?

Adenylyl (adenyl) cyclase via G-proteins

What is the effect of D1 receptors on adenylyl cyclase?

Stimulate adenylyl cyclase

What is the effect of D2 receptors on adenylyl cyclase?

Inhibit adenylyl cyclase

What can stimulation of dopamine receptors change?

Enzyme activity and gene expression

Are noradrenaline and adrenaline excitatory or inhibitory?

Both are generally excitatory neurotransmitters, but adrenaline is present at lower levels

Where are noradrenaline and adrenaline mostly synthesised?

Sympathetic ganglion cells located near the spinal cord or abdomen

What role does noradrenaline play in the autonomic nervous system?

It is a major neurotransmitter that helps coordinate motor behaviour

What are the functions of noradrenaline in the brain?

Regulates attention, arousal, memory, and the sleep–wake cycle

What are the functions of noradrenaline in the body?

Boosts cardiovascular function and prepares muscles for activity

Where do noradrenergic neurones originate?

The locus coeruleus

What physiological response are noradrenaline and adrenaline involved in?

Fight-or-flight responses

Where is adrenaline used as a neurotransmitter in the brain?

Neurones in the medulla oblongata

How many types of adrenergic receptors are there?

Nine types of adrenergic receptors

Can dopamine activate adrenergic receptors?

Yes, dopamine can activate certain adrenergic receptors at higher doses

What are the α1 adrenergic receptor subtypes?

α1A, α1B, α1D

Which G-protein is associated with α1 receptors?

Gq

What is the main signalling pathway of α1 receptors?

Increased phospholipase C → increased IP₃ and DAG → increased Ca²⁺

What are the effects of α1 receptor activation?

Smooth muscle contraction, including vasoconstriction and pupil dilation

What are the α2 adrenergic receptor subtypes?

α2A, α2B, α2C

What is the G-protein associated with α2 receptors?

Gi

What is the main signalling pathway of α2 receptors?

Decreased adenylyl cyclase → decreased cAMP

What are the main effects of α2 receptor activation?

Inhibition of neurotransmitter release (autoreceptors) and vasoconstriction

What is the β1 adrenergic receptor subtype?

β1

What is the G-protein associated with β receptors?

Gs

What is the main signalling pathway of β1 receptors?

Increased adenylyl cyclase → increased cAMP

What are the main effects of β1 receptor activation?

Increased heart rate and increased contractility

What is the β2 adrenergic receptor subtype?

β2

What is the main signalling pathway of β2 receptors?

Increased adenylyl cyclase → increased cAMP