Neurotransmitter Systems

What is the criteria for a chemical to be classified as a neurotransmitter?

1. Synthesized and stored in presynaptic neuron

2. Released by presynaptic axon terminal

3. Produces response in postsynaptic cell

Immunocytochemistry

Antibodies label a protein (synthesizing enzyme or transporter) in cells

MUST BE MADE AND STORED IN THE PRESYNAPTIC NEURON

In situ hybridization (ISH,FISH)

Labeled probes bind mRNA: shows which cell synthesizes proteins/peptides. Radioactive probes are used to visualized by autoradiography or florescence

MUST BE MADE IN THE PRESYNAPTIC NEURON

Brain Slice Stimulation

Electrically stimulates a slice, collect and measure the released chemicals

Can only be activated only

Optiogenetics

Channelrhodopsin is expressed only in a genetically defined population, and activates under blue light

Microiontophoresis

Apply tiny amounts of a transmitter onto a neuron and compares the response to the response of synaptic stimulation

Agonists

Drugs that activate the receptor; used to identify receptor subtypes

Antagonists

Drugs that inhibits or blocks the receptor; used to identify receptor subtypes

Ligand-Binding Autoradiography

A radioactive ligand binds a receptor and shows where receptors are located

Nicotine

Agonist at nicotinic ACh receptors (ionotropic)

Curare

Antagonist at nicotinic receptors at NMJ

Atropine (belladonna)

Antagonist at muscarinic receptors

Muscarine (fly agaric mushrooms)

Agonist at muuscarinic receptors

Glutamate subtype agonist

AMPA, NMDA, kinate each bind only their own glutamate receptor subtypes; used to identify subtypes

What are the three major neurotransmitter systems?

Amino Acids

Amines

Peptides

What neurotransmitter does not fit in the major categories?

Acetylcholine (ACh)

How are Amino Acids and Amines made

They are synthesized by enzymes in the terminal and loaded into vesicles by transporters

Peptides

made from precursor peptides in the soma, packaged into secretory granules, and transported to the terminal

What is Dale’s principle

One Neuron, One Transmitter.

Co-Transmitters

There are many exceptions, and if two transmitters are released its called “co-transmitters”

typically an amino acid or amine plus a peptide

Acetylcholine (ACh) Synthesis

Acetyl CoA + Choline (Rate-limiting step) via choline acetyltransferase (ChAt)

Acetylcholine (ACh) Breakdown

Acetylcholinestrase (AChE) is the enzyme that breaks it down

Choline is transported back to the cell

Acetic acid is left over

Acetylcholine (ACh) Function

Its found in all motor neurons in the brain and spinal cord

what are the three Catecholamines

Dopamine

Norepinephrine

Epinephrine

Catecholamines Synthesis

Starts with Tyrosine + tyrosine hydroxylase (rate limiting step)

Catecholamines Breakdown

Its recycled back to the cell via reuptake pumps and then broken down by Monoamine oxidase (MAO) and CMT

Catecholamines Function

Movement, mood, attention, and visceral function

Why is Tyrosine Hydroxalyse the rate limiting step

Decreases the number of neurotransmitters released via end-product inhibition and speeds up release with elevated calcium levels

Serotonin Synthesis

From Tryptophan to tryptophan hydroxylase (rate limiting step)

Serotonin Breakdown

Reuptake and then breakdown by MAO

Serotonin Function

regulation of mood, emotional behavior and sleep

Which three Amino Acids are Neurotransmitters

Glutamate, Glycine, and GABA

Glutamate Synthesis

Glutamine via glutaminase

also made from glucose by enzymes

Glutamate Breakdown

Reuptake into terminal and astrocytes

Glutamate Function

major excitatory NT

GABA Synthesis

From glutamate by glutamic acid decarboxylase (GAD)

GABA Breakdown

Reuptake into terminals and astrocytes; metabolized by GABA transaminase

GABA Function

Major inhibitory transmitter, not used to build proteins

ATP Function

Is typically co-released with classical transmitters and acts on ionotropic purinergic receptors (cation channels, excitatory)

ATP Breakdown

its broken down to AMP and adenosine, which acts on its own receptors

Caffine

Blocks adenosine receptors giving a stimulating effect (antagonist)

Endocannabinoids

Retrograde messengers (post synaptic to pre synaptic) not packaged into vesicles, but is lipid soluble, calcium dependent, released in response to high synaptic activity

Nitric Oxide

Gas made from arginine, small and membrane permeable; possible retrograde messenger. Hard to study because it rapidly metabolized

implicated in nicotine and cocaine effects

Transmitter-Gated Channels

Fast synaptic transmission that regulates flow of large currents

Is able to differentiate between similar ions

What is the basic structure of the transmitter-gated channels

Pentamer: Five protein subunits

Glutamate-Gated Channels

three subtypes: AMPA, NMDA, and kainate

AMPA

AMPA receptors pass Na+ (K+) and produce the fast EPSP

NMDA

NMDA are permeable to Ca2+ and are voltage dependent

Blocked by Mg2+ at rest

Coincidence Detector

NMDA receptors pass currents only when glutamate is bound AND the membrane is depolarized

What happens with excess or inadequate GABA levels

Too much = loss of consciousness and coma

Too little = siezures

NMDA Lesions

Kills neuron cell bodies in injected areas while sparing axons passing through due to excitonic

G-Protein-Coupled Receptors Structure

Single polypeptide with seven membrane-spanning alpha-helices

more than 100 types

What happens as transmitter binds to G-Protein-Coupled Receptors

It exchanges GDP for GTP, which turns on the protein and its subunits interact with effector proteins to inhibit or excite systems

Shortcut Pathway

Receptor to G-protein to ion channel directly

fast and local

Second Messenger cascade

G-protein activates an enzyme that produces a second messenger which further activates further enzymes

Protein Kinase vs Phosphates

Kinase adds a phosphate group to proteins, changing their conformation and activity

Phosphates remove phosphate groups, reversing the effect

Signal Amplification

One receptor activates many G-proteins, each enzyme makes many second messenger molecules and each kinase phosphorylates many proteins

Divergence

one transmitter activates several receptor subtypes and multiple effectors.

Convergence

Different transmitter through their receptors act on the same effector system