CNSC EXAM 3

What are the 2 components of chemical signaling?

• Molecular signal (neurotransmitter)

• Receptor (receives and transduces signal)

major classes of small-molecule neurotransmitters

• Acetylcholine (ACh)

• Amino acids: Glutamate, GABA, glycine

• Biogenic amines: Dopamine, norepinephrine, epinephrine, serotonin, histamine

Major excitatory vs. inhibitory amino acid neurotransmitters

• Glutamate: Excitatory

• GABA + glycine: Inhibitory

Ionotropic receptors

Ligand-gated ion channels that open directly when a neurotransmitter binds.

Metabotropic receptors

G-protein-coupled receptors (GPCRs) that indirectly regulate ion channels or other cellular processes.

Structure of ionotropic receptors

Usually 4–5 protein subunits that form an ion channel across the membrane.

Examples of ionotropic receptors

• Glutamate: NMDA, AMPA, kainate

• Acetylcholine: Nicotinic

• Serotonin: 5-HT₃

• GABA_A

• Glycine

• ATP: P2X

How do metabotropic receptors work?

Neurotransmitter binds → G protein activates → regulates ion channels or intracellular signaling.

Metabotropic structure

Typically one protein with 7 transmembrane domains.

What are the 3 major families of ionotropic receptors?

• Ionotropic glutamate receptors: AMPA, NMDA, kainate

• Cys-loop receptors: GABA_A, glycine, nicotinic ACh, 5-HT₃

• ATP-gated channels: P2X

Examples of metabotropic receptors

• Glutamate: mGluR

• GABA: GABA_B

• ACh: Muscarinic

• Dopamine, norepinephrine, epinephrine, histamine

• Serotonin: Most 5-HT receptors

• ATP/other purines: P2Y and related GPCRs

Structure of nicotinic ACh receptors (nAChRs)

5 subunits, each with 4 transmembrane helices (M1–M4).

Which parts of nAChR bind ACh and form the pore?

• α subunits: Bind ACh

• M2 helices: Line the ion pore

How is acetylcholine (ACh) synthesized?

choline + acetyl-CoA → ACh

How is ACh removed after release?

Acetylcholinesterase (AChE) breaks ACh into acetate + choline.

How is choline recycled after ACh breakdown?

Na⁺/choline transporter takes choline back into the presynaptic terminal for ACh resynthesis.

Nicotinic ACh receptors are _______, whereas muscarinic ACh receptors are ______.

ionotropic; metatropic

What causes myasthenia gravis?

Autoantibodies attack postsynaptic nicotinic ACh receptors at the neuromuscular junction → reduced muscle activation.

What are the symptoms of myasthenia gravis?

Muscle weakness and fatigue

what happens to the eyes during myasthenia gravis?

often beginning with drooping eyelids (ptosis).

How is myasthenia gravis treated with AChE inhibitors?

Neostigmine inhibits acetylcholinesterase

→ ACh stays longer in the synaptic cleft

→ improves muscle activation.

In myasthenia gravis, EPPs are _____ because fewer functional ACh receptors are available.

smaller

Irreversible acetylcholinesterase (AChE) inhibitors

Organophosphates (insecticides/nerve agents)

Organophosphates (insecticides/nerve agents)

block AChE → ACh accumulates → overstimulation and paralysis.

How is organophosphate poisoning treated?

Atropine and Pralidoxime (2-PAM)

Atropine

Blocks muscarinic ACh receptors

Pralidoxime (2-PAM)

Reactivates AChE if given early

Muscarinic ACh receptors

Metabotropic GPCRs with 7 transmembrane domains that signal through G proteins.

Glutamate

Most common excitatory neurotransmitter in the CNS (over half of synapses).

How is glutamate synthesized?

Glutamine → glutamate

VGLUT

Loads glutamate into synaptic vesicles.

EAAT

Removes glutamate from the synaptic cleft into neurons/glia.

Ionotropic glutamate receptors

• AMPA

• NMDA

• Kainate

Glutamate is taken up by glial cells → converted to glutamine → returned to neurons →

converted back to glutamate.

Why are NMDA receptors blocked at resting potential?

Mg²⁺ blocks the NMDA channel pore at resting membrane potential.

What is required to activate NMDA receptors?

• Glutamate + glycine bind

• Depolarization removes Mg²⁺ block (often via AMPA receptors)

What is long-term potentiation (LTP)?

A long-lasting increase in synaptic strength following synaptic activity.

How does NMDA activation cause early LTP?

Ca²⁺ enters → AMPA receptors are phosphorylated → stronger synaptic response.

How does NMDA activation cause late LTP?

Ca²⁺ triggers gene transcription + protein synthesis → long-lasting synaptic strengthening.

How is glutamate removed from the synaptic cleft?

Reuptake by Excitatory Amino Acid Transporter (EAAT) transporters.

How is ACh removed from the synaptic cleft?

Enzymatic breakdown by acetylcholinesterase (AChE).

mGluRs

Metabotropic glutamate receptors (GPCRs) that produce slow excitatory or inhibitory responses.

Group I mGluRs (1, 5)

Excitatory, Gq-coupled → activates PLC and increases NMDA activity.

Group II mGluRs (2, 3)

Inhibitory, Gi/o-coupled → ↓ cAMP, ↓ transmitter release.

Group III mGluRs (4, 6, 7, 8)

Inhibitory, Gi/o-coupled → ↓ cAMP, ↓ transmitter release.

GABA and glycine

Major inhibitory neurotransmitters.

How is GABA synthesized?

Glutamate → GABA

GAD (glutamate decarboxylase)

Enzyme

VIATT

Loads GABA into vesicles

GAT

Removes GABA from synaptic cleft (reuptake)

GABA_A and GABA_C receptors

Ionotropic Cl⁻ channels that typically produce inhibition.

Benzodiazepines

↑ Frequency of GABA_A channel opening

Barbiturates

↑ Duration of channel opening

When does Cl⁻ influx cause hyperpolarization?

When ECl is more negative than resting Vm, Cl⁻ enters → membrane hyperpolarizes.

High intracellular Cl⁻ → GABA opens Cl⁻ channels →

Cl⁻ exits → depolarization.

Low intracellular Cl⁻ → GABA opens Cl⁻ channels →

Cl⁻ typically enters → hyperpolarization.

NKCC1 (Na⁺/K⁺/Cl⁻)

Brings Cl⁻ IN → high intracellular Cl⁻

KCC2 (K⁺/Cl⁻)

Moves Cl⁻ OUT → low intracellular Cl⁻

Developing neuron

High Cl⁻ inside → GABA depolarizes.

Mature neuron

Low Cl⁻ inside → GABA usually inhibits.

Open K⁺ channels

hyperpolarization

Inhibit Ca²⁺ channels

reduced neurotransmitter release

How do presynaptic GABA_B receptors affect neurotransmitter release?

Inhibit Ca²⁺ entry → decrease neurotransmitter release (GABA, glutamate, dopamine, etc.).

What is a GABA_B autoreceptor?

A presynaptic receptor activated by GABA from its own neuron, reducing further GABA release.

Vigabatrin

Inhibits GABA breakdown (GABA-T)

Tiagabine

Inhibits GABA reuptake (GAT)

GABA_B receptor agonist

→ increases inhibitory signaling.

Baclofen

GABA_B receptor agonis

What is the catecholamine synthesis pathway?

Tyrosine → L-DOPA → Dopamine → Norepinephrine → Epinephrine

What enzyme converts tyrosine → L-DOPA?

Tyrosine hydroxylase (TH)

What enzyme converts L-DOPA → dopamine?

DOPA decarboxylase (AADC)

What enzymes convert dopamine → norepinephrine → epinephrine?

• Dopamine → Norepinephrine: Dopamine β-hydroxylase (DBH)

• Norepinephrine → Epinephrine: PNMT

How do catecholamines act as neuromodulators in the CNS?

They modify EPSPs/IPSPs and neuronal excitability rather than directly producing fast EPSPs/IPSPs.

What determines the effects of catecholamines on neurons?

• Receptor subtype

• Intracellular signaling pathway

• Brain region/circuit

• Postsynaptic cell type

___________ can increase tyrosine hydroxylase activity and catecholamine synthesis.

Stress, caffeine, nicotine, and morphine

What are the major functions of dopamine?

• Movement

• Reward/motivation

• Addiction

• Mood

What are the major functions of norepinephrine?

• Attention

• Wakefulness

• Stress response

• Pain inhibition

Dopamine neurons origination

Substantia nigra + ventral tegmental area (VTA)

Norepinephrine neurons origination

Locus coeruleus

What causes Parkinson's disease?

Loss of dopamine-producing neurons in the substantia nigra → reduced dopamine signaling and impaired movement.

What is the defining feature of addiction?

Compulsive drug use despite negative consequences.

Positive vs. negative reinforcement in addiction

Positive = gain pleasure | Negative = remove discomfort

What is the main dopamine reward pathway?

VTA → nucleus accumbens (NAc)

Tolerance

Decreased drug effect with repeated use.

Sensitization

Increased drug response with repeated use.

Dependence

Adaptation to repeated drug use; stopping may cause withdrawal.

Addiction

Compulsive use despite harmful consequences.

VMAT

Loads dopamine into vesicles.

DAT

Reuptakes dopamine from the synaptic cleft.

MAO

Breaks down monoamines.

COMT

Breaks down catecholamines.

What happens when MAO is inhibited?

Less dopamine breakdown → increased dopamine availability.

How does cocaine affect dopamine?

Blocks DAT → prevents dopamine reuptake → dopamine accumulates in the synaptic cleft.

How do amphetamines affect dopamine?

Increase dopamine release and reverse DAT, causing dopamine to move into the synaptic cleft.

How is norepinephrine (NE) removed from the synaptic cleft?

NET (norepinephrine transporter) reuptakes NE into the presynaptic neuron.

What receptors do norepinephrine and epinephrine activate?

α- and β-adrenergic receptors, both metabotropic GPCRs.

How do NRIs and SNRIs affect norepinephrine?

• NRIs: Block NE reuptake.

• SNRIs: Block NE and serotonin reuptake.

Clonidine

α₂ agonist → decreases NE release.

Yohimbine

α₂ antagonist → increases NE release.