S.T. Exam 3 Flashcards

What determines the effect of a neurotransmitter at a synapse?

The type of receptor on the post synaptic cell.

Do neurotransmitters bind only one receptor type?

No

What are the two major classes of receptors?

Ionotropic and Metabotropic

What are ionotropic receptors?

Ligand gated ion channels

What are metabotropic receptors?

Receptors that activate second messenger systems and alter cell metabolism.

Types of metabotropic receptors?

G-protein, Tyrosine Kinase, Cytoplasmic

Ionotropic onset/termination speed?

Fast

Metabotropic onset/termination speed?

Slow

Ionotropic response ratio?

1:1

Metabotropic response ratio?

Amplified

Why do metabotropic receptors allow more diversity?

Due to second messenger effects

Where are ionotropic receptors located?

Near transmitter release sites

Where are metabotropic receptors located?

Distant from release sites

Where can both receptor types be found?

Presynaptic, post synaptic, glial cells.

Name transmitters that bind both ionotropic and metabotropic receptors.

Ach, GABA, Glutamate

Ionotropic ACh receptor type?

Nicotinic

Metabotropic ACh receptor type?

Muscarinic

Muscle nAChR activation level?

µM ACh

Neuronal nAChR affinity?

nM ACh

Why does smoking affect neuronal but not muscle receptors?

Nicotine levels (~nM) activate neuronal receptors only

What ion enters with Na⁺ in neuronal nAChRs?

Ca2+

Major ionotropic receptor families?

Pentameric "cys-loop"

Glutamate

Trimeric

TRP

What receptors are included in the cys loop family?

Nicotinic ACh

GABA-A

Glycine

Serotonin (ionotropic)

How many subunits in Nic Receptor?

5

Composition of Nic receptor subunits?

2 alpha, 1 beta, 1 gamma, 1 delta

How many transmembrane regions per subunit in Nic?

4 (M1-M4)

Which region lines the pore in Nic?

M2

Which subunits bind ACh in Nic?

Alpha subunits

How many ACh binding sites in Nic?

2

What happens with one ACh bound?

Channel flickers (brief opening)

What happens with two ACh bound?

Normal opening

What increases opening probability?

Higher ACh concentration

What blocks Ach binding?

Alpha-bungarotoxin

Curare

Which ions pass through nAChRs?

Na⁺

K⁺

Ca²⁺

Which subtype is highly Ca²⁺ permeable?

α7

NMJ receptor affinity?

Low (µM)

CNS receptor affinity?

High (nM)

Do CNS receptors always have γ and δ subunits?

No

α4β2 function?

Addiction & reward

α7 structure?

Homomeric (5 α7 subunits)

How many bindings needed for α7 activation?

3

α7 function?

Cognition

Where is α7 abundant?

Hippocampus

Time for nicotine to reach brain?

10-20 seconds

Where does addiction begin?

At the synapse

Nicotine addiction mechanism 1

Depolarization → VG Ca²⁺ channels

Nicotine addiction mechanism 2

Direct Ca²⁺ entry

Results of nicotine addiction

Increased dopamine in reward pathway

What block is removed during nic addiction?

Mg²⁺ block of NMDA receptors resulting in increased calcium entry.

Key pathway in addiction?

VTA → Nucleus Accumbens

What happens if antagonist injected into VTA?

Stops nicotine self-administration

What happens if antagonist injected into nucleus accumbens?

No effect

Critical receptor for addiction?

α4β2

β2 knockout effect?

No nicotine self-administration

How does nicotine affect the firing of dopamine neurons in the VTA?

It increases the firing rate from "tonic" (regular, slow) to "phasic" (burst firing), which significantly increases dopamine release.

What role does the a7 nAChR play in nicotine addiction?

a7 receptors are often located presynaptically on glutamate terminals. Nicotine binds to them, increasing calcium influx and stimulating glutamate release onto dopamine neurons, further driving their activity.

How does cigarette smoke (aside from nicotine) prolong dopamine effects?

It contains alkaloids (like Harman) that inhibit Monoamine Oxidase (MAO), the enzyme responsible for breaking down dopamine. This inhibition can last up to 30 days after quitting.

What is the "Dual-Reinforcement Model" of nicotine?

1. Primary Reinforcement: Nicotine directly triggers dopamine release. 2. Secondary Reinforcement: Nicotine enhances the reward value of "non-drug" stimuli (e.g., the smell of a bar, a coffee break).

Homy many subunits make up an ionotropic glutamate receptor, and how many transmembrane domains does each subunit have?

4 subunits and 3 domains

What is the exact subunit composition of an NMDA receptor?

2 GluN1 proteins and 2 GluN2 proteins.

What are the 2 mandatory agonists for NMDA receptor activation?

Glutamate and Glycine/D-Serine

Where does glutamate bind on an NMDA receptor?

GluN2 subunit

Where does glycine/D-serine bind on an NMDA receptor?

GluN1 subunit

NMDA permeability to Ca2+

high

Explain the mechanism of the Mg2+ block

At resting Vm, Mg2+ physically blocks the pore due to electrostatic attraction.

Explain the mechanism behind the removal of the Mg2+ block?

Post-synaptic DP electrostatically repels Mg2+ out of the pore.

Why is the NMDA receptor a coincidence detector?

It requires 2 simultaneous events to open (glutamate release and depolairzation)

What inhibitors target NMDA receptors?

H+, Zinc, Polyamines, Ifenprodil, Ketamine, Memantine, PCP/MK-801.

What are the key differences between AMPA and NMDA receptors regarding Mg2+?

AMPA is not blocked by Mg2+ at rest.

What are the key differences between AMPA and NMDA receptors regarding kinetics?

AMPA is fast (peaks and decays quickly).

Role of AMPA

AMPA provides the initial depolarization to unblock NMDA.

Define silent synapses

Synapses that only have NMDA receptors, no AMPA. They show no current at resting Vm even if glutamate is released.

To which structural family do GABA-A and Glycine receptors belong?

Pentameric (ligand gated Cl- channels)

Explain shunting inhibition

When GABA-A channels open, they increase membrane conductance (by reducing resistance). This creates a short circuit where the excitatory current leaks out through Cl- pores before it can reach the axon hillock.

Describe the Developmental Shift of GABA-A action (NKCC1 vs. KCC2).

Immature: NKCC1 pumps Cl- in. Internal Cl- is high. GABA causes Cl- efflux leading to depolarization.

Mature: KCC2 pumps Cl- out. Internal Cl- is low. GABA causes Cl- influx leading to hyperpolarization.

How do benzodiazepines affect the GABA-A receptor?

They are positive allosteric modulators and bind at a site distant from GABA, destabilizing the closed state making it easier for the channel to open when GABA is present.

What is the specific antagonist for Glycine receptors, and how is the synapse cleared?

Strychnine. A pump removes glycine from the cleft to maintain sensitivity.

What is "Excitotoxicity" and what causes it?

Over-activation of NMDA receptors leading to excessive Ca2+ influx.

What is a "Back-Propagating Action Potential" and why is it important for NMDA receptors?

It is an action potential that starts at the axon hillock but travels backward into the dendrites. It provides the depolarization necessary to repel the Mg2+ block from NMDA, allowing them to open if glutamate is also present.

Define the "Dual-Reinforcement Model" of nicotine

1. Primary: Nicotine directly triggers dopamine release in the VTA. 2. Secondary: Nicotine enhances the reward value of "non-drug" environmental stimuli (like the smell of a bar or coffee).

How does the NMDA receptor contribute to "Hebbian Plasticity"?

Because it is a coincidence detector (requiring both pre- and post-synaptic activity), it ensures that the synapse is only strengthened when both neurons are active at the same time ("Cells that fire together, wire together").