CBNS Lecture 6- Neurotransmitter systems

Foundations

1. NT possibilities

a) What is Dale’s Principle?
→ A neuron releases the same neurotransmitter at all its synapses

b) What are co-transmitters?
→ When a neuron releases multiple neurotransmitters (e.g., amine + peptide)

c) What does “-ergic” mean?
→ Refers to the neurotransmitter used
→ Example: cholinergic, GABAergic, glutamatergic

2. Criteria for labeling a NT

a) must be synthesized and stored in the presynaptic terminal

b) must be released at the terminal

c) must have the same effect when applied experimentally

Studying NT systems

1. In situ hybridization
   → Detects mRNA → shows where proteins are made

2. Immunocytochemistry
   → Uses antibodies to locate specific molecules in cells

Studying Synaptic Mimicry

1. Microiontophoresis
   → Applies tiny amounts of a substance to test postsynaptic effects

2. Microelectrode
   → Measures changes in membrane potential

Ach

1. Why is ACh important?
   → First discovered neurotransmitter
   → Major transmitter at neuromuscular junction

2. ACh synthesis enzyme
   → Choline acetyltransferase (ChAT)

3. ACh breakdown enzyme
   → Acetylcholinesterase (AChE)

Catecholaminergic neurons

What are catecholamines derived from?
→ Tyrosine

Three main catecholamines
→ Dopamine
→ Norepinephrine
→ Epinephrine

Key enzymes in catecholamine synthesis
→ Tyrosine hydroxylase (rate-limiting step)
→ Dopa decarboxylase
→ Dopamine β-hydroxylase
→ PNMT

1. Tyrosine → L-DOPA Enzyme: Tyrosine hydroxylase (TH) What happens: A hydroxyl group (–OH) is added to tyrosine Importance: This is the rate-limiting step (slowest, tightly regulated)

2. L-DOPA → Dopamine Enzyme: DOPA decarboxylase What happens: A carboxyl group (–COOH) is removed (decarboxylation) Result: Formation of dopamine, an important neurotransmitter

3. Dopamine → Norepinephrine Enzyme: Dopamine β-hydroxylase (DBH) What happens: A hydroxyl group (–OH) is added to the side chain Result: Norepinephrine (noradrenaline)

4. Norepinephrine → Epinephrine Enzyme: Phenylethanolamine N-methyltransferase (PNMT) What happens: A methyl group (–CH₃) is added to the amine Result: Epinephrine (adrenaline)

Functions of catecholamines
→ Movement
→ Mood
→ Attention
→ Visceral functions

Serotoninergic neurons

Serotonin is derived from
→ Tryptophan

Functions of serotonin
→ Mood
→ Sleep
→ Emotional behavior

Serotonin synthesis enzymes
→ Tryptophan hydroxylase
→ 5-HTP decarboxylase

1. Tryptophan → 5-Hydroxytryptophan (5-HTP) Enzyme: Tryptophan hydroxylase What happens: A hydroxyl group (–OH) is added to the aromatic ring Key point: This is the rate-limiting step (like tyrosine hydroxylase in the other pathway)

2. 5-HTP → Serotonin (5-HT) Enzyme: Aromatic L-amino acid decarboxylase (aka 5-HTP decarboxylase) What happens: The carboxyl group (–COOH) is removed Result: 5-Hydroxytryptamine (serotonin, 5-HT)

What do SSRIs do?
→ Block serotonin reuptake → increase serotonin levels

Amino acidergic neurons

1. Nt’s

• glu

• gaba

• glycine

2. Gaba synthesis: Glu to gaba (GAD)

3. VESICULAR TRANSPORTERS- Presynaptic site

a) vGAT
→ Loads GABA into vesicles

b) vGlut
→ Loads glutamate into vesicles

Receptor subtypes

1. ACh Receptors

Things have been done to inhibit ACH receptors …

a) Nicotonic

• Curare darts block normal synaptic transmission of NMJ (Ach to nicotonic receptors)

• Either mimics ach action or blocks

b) Muscarine

• Atropine found to block muscarine

2. Glutamate Receptors:

a) AMPA (transmission)- permeable to Na and K

b) NMDA (plasticity)- permeable to Na, K, and Ca

• depol occurs on presynaptic side and releases Glu

• Blu binds to AMPA and it opens allowing Na and K to rush in (depol on post)

• depol causes Mg block to leave NMDA allowing for Na, k, and Ca to flow in (LTP)

GABA receptors

1. GABAa

a) ionotropic

b) inhibitory

2. GABAb

a) metabatropic

b) GPCRs = turn outside signal into an inside cellular response using G proteins

• structure: 7 membrane spanning alpha helices (one protein crosses the membrane 7 times) sitting in the cell membrane

• Steps:

  • Signal binds = ligand (nt or hormone) binds to the GPCR on outside

  • G protein gets activated =

    • G protein has 3 parts alpha, beta, and gamma

    • when activated GDP becomes GTP on the apha subunit

    • separates alpha and beta

  • Cell Response =

    • separated alpha and beta parts go activated other proteins (effectors)

    • cellular response BANG

  • Reset =

    • apha subunit goes opposite way (GTP to GDP)

    • another round thank q

c) Effector Systems

the targets of the G protein that create a response

1. Shortcut pathway (ion channels):

• the G protein directly opens/closes a channel

• immediate effect

• fast and direct

• Ex: ach- autonomic nervous system

2. Secondary (enzymes):

• G protein activates enzyme inside the membrane

• the enzyme makes second messengers

• slower but stronger/a mplified

more on GPCR effector systems

so yk the basics but now…

1. Push Pull signaling

Two different G proteins control the same enzyme (cAMP) but in opposite ways

a) Gs

• activates cAMP and PKA

b) Gi

• inhibits cAMP and PKA

2. Gq

Calcium pathway

• Gq activates phospholiphase (PLC)

• PLC splits one molecule into IP3 and DAG

• Then =

  • Ip3 goes to the ER and releases Ca2+

  • DAG activates PKC

• Final = calcium rises and there is an activation of enzymes

3. Amplification pyramid = small signal leads to big response