Neuroscience Chapter 3

Categories of Neurotransmitters

Neuropeptides: 3-36 AA

Small-molecule Neurotransmitters

Acetylcholine

1st identified

Neuromuscular junctions, synapse at vagus nerve/cardiac muscle fibers, ganglia of visceral motor system, and sites in CNS

synthesized in terminal from Acetyl CoA and Choline(sodium-dependent choline cotransporter)

ACh transporter packages ~10,000 into vesicle

Acetylcholinesterase

Acetylcholinesterase hydrolyzes into acetate and choline(recycled)

5,000 ACh/1AChE/per second

Organophosphates: chemical warfare agents: inhibits AChE causing ACh buildup, neuromuscular paralysis

Insectisides

Nicotinic Acetylcholine Receptor

Allows cations to enter: Na, K, Ca

NM: made up of 5 subunits 2 alpha, 1 beta, 1 delta, 1 gamma/epsilon

2 ACh on alpha to open

neuronal AChR: made of 3 alpha and 2 beta: pore is wider than typical ion channel so allows multiple cations to enter

Muscarinic AChR

mediates most of the effects of ACh in the brain

Metabotropic

5 subtypes: each coupled to different G-protein

Highly expressed in corpus striatum: open K channels inhibitory effect on dopamine-mediated motor effects

in hippocampus, closes K channels so excitatory

glutamate

most important for normal brain function

estimated that half of all brain synapses release this neurotransmitter

during brain trauma, excessive release of glutamate can cause excitotoxic brain damage

it is a non-essential AA that can’t cross the blood brain barrier

main precursor is glutamine

glutamate glutamine cycle

glutamine taken up by SAT2

vesicular glutamate transporter(VGLUT)

glutamine synthesis

maintains glutamate levels and rapidly removes it from synapse

ionontropic glutamate receptors

3 types: AMPA, NMDA, and kainate receptors

all allow Na to enter cells and potassium to exit: always produce excitatory postsynaptic responses

most excitatory synapses have both AMPA and NMDA receptors

Each differs in the postsynaptic response caused by binding

AMPA receptors

composed of 4 subunits

when glutamate interacts with binding site, it causes the clam shell structure to shut, thereby opening pore

NMDA receptors

also allows Ca that can act as second messenger

Mg gating

needs glutamate depolarization and co-agonist glycine

NMDA receptor shape

made with 4 subunits: there are 3 groups with 7 total

GluN2 subunits bind glutamate: GLuN1 and GluN3 blind glycine

usually made of 2 glutamate and 2 glycine binding subunits

has clam shell shaped ligand binding sites

has unique domain believed to bind calcium conferring calcium permeability

metabotropic NMDA receptors

most lead to inhibition of Na and Ca channels in the postsynaptic neuron

cause slower postsynaptic responses that can be either excitatory or inhibitory

physiological roles quite varied

GABA synthesis

GABA and glycine are the NTs used at most inhibitory synapses in the CNS

1/3 of synapses in the brain use GABA as inhibitory NT

Precursors: glucose, pyruvate, or gluatmine

Pyridoxal Phosphate is cofactor derived from vitamin B6(infant deaths due to lack of vitamin B6 in infant formula caused seizures)
vesicular inhibitory AA transporter into vesicles(VIAAT)

GABA removal

glial cells and neurons contain GATs which transport the GABA into the cells

most GABA converted to succinate by 2 mitochondrial enzymes: GABA transaminase and succinic semialdehyde dehydrogenase

other pathways for degradation: leads to production of gamma hydroxybutyrate: a date rape drug

oral administration leads to euphoria, memory deficits, and unconsciousness. probably due to effects on GABA synapses in CNS

GABA receptors: GABA_A

2 types: GABA_A(iono) and GABA_B(metabo)

GABA_A are gated chloride channels: adult neurons vs developing neurons

19 types of GABA_A subunits with receptor usually made from 5 subunits

many drugs bind to this receptor and activate it

GABA_B receptors are inhibitory. Opens K channels and blocks Ca channels

Glycine synthesis

½ of inhibitory synapses in SC use this NT

serine converted into glycine

transported into vesicles by VIAAT same as GABA

rapidly removed by glycine transporters

glycine receptors

5 subunits

blocked by strychnine

ligand gated Cl channels

Biogenic Amines

Active in CNS and PNS

implicated in wide range of disorders including psychiatric disorders

synapse important in psychotherapy with drugs affecting synthesis, receptor binding or catabolism of NT

many abused drugs act on these pathways

5 members of this group: catecholamines(dopamine, norepinephrine, epinephrine) histamine and serotonin

all catecholamines are derived from tyrosine

dopamine

present in several brain regions but major region is corpus striatum(receives input from substantia nigra and plays role in coordination of body movements)

parkinson’s: neurons in substantia nigra degenerate

also believe to play a role in motivation, reward, and reinforcement

drugs of abuse affect dopaminergic neruons

dopamine synthesis

tyrosine converted by 2 enzymes

loaded into vesicles by vesicular monoamine transportor(VMAT)
reuptake by presynaptic neuron and glial cells using DAT

cocaine and amphetimines inhibit DAT

monoamine oxidase(MAO) and (COMT) degrade dopamine

MAO used as antidepressent

dopamine receptors

all are metabotropic: 5 receptors

either activate or inhibit cAMP

activation contributes to complex behaviors

agonists for one receptor cause hyperactivity and repetitive behavior in animals

activation of a different receptor in medulla inhibits vomiting. agonist used for poisoning or drug overdose

antagonists can cause catalepsy, state where difficult to do voluntary movement suggesting role in some psychoses

norepinephrine

used in locus coeruleus a brainstem nucleus that projects diffusely to a variety of forebrain targets and influences sleep and wakefulness, arousal, attention, and feeding behavior

also the major NT of the sympathetic nervous system

norepinephrine synthesis

synthesized and loaded into vesicles using the same VMAT as dopamine

cleared by norepinephrine transporter (NET)

destroyed by MAO and COMT

amphetamines also inhibits NET

mutation in NET gene causes orthostatic intolerance, disorder that produces lightheadedness while standing up

norepinephrine receptors

alpha and beta adrenergic receptors

all metabotropic

2 subtypes of alpha

alpha 1 cause slow depolarization by inhibiting K channels

alpha 2 cause a slow hyperpolarization by activation of different K channels

agonist and antagonists of receptors used clinically for arrhythmias to migraines

epinephrine

adrenaline

in brain at lower levels than other catecholamines and is present in fewer brain neurons

mainly found in medulla and lateral tegmentum where they project to thalamus and hypothalamus

regulate respiration and cardiac function

synthesis

NET can transport

uses alpha and beta adrenergic receptors

histamine

found in neurons in the hypothalamus that send out projections to almost all regions of brain and spinal cord

can mediate arousal and attention and control reactivity of vestibular system

may influence blood flow in brain based on effects of histamine from mast cells

synthesis: vesicles VMAT

no transporter

degraded by histamine methyltransferase and MAO

histamine receptors

4 types: all metabotropic

antihistamines like Benadryl act as sedatives by interfering with histamine in CNS(antagonist)

antagonists of H1 receptor help prevent motion sickness, probably because of histamines role in vestibular system

H2 receptors control gastric acid secretion. receptor antagonists used to treat

serotonin

AKA 5-hydroxytryptamine

found primarily in groups of neurons in the raphe region of the pons and upper brainstem, which have widespread projections to the forebrain

regulates sleep and wakefulness

antipsychotic drugs that treat depression and anxiety act on serotonergic pathways

serotonin regulation

tryptophan is an essential dietary supplement

tryptophan-5-hydroxylase is rate limiting stem

VMAT used to get into vesicles

transport back into presynaptic terminal by SERT. SSRIs inhibit this

Degraded by MAO

serotonin metabotropic receptors

most 5-HT receptors are metabotropic

implicated in circadian rhythms, motor behaviors, emotional states, and state of mental arousal

impairments implicated in depression, anxiety disorder, and schizophrenia

LSD is believed to cause hallucination by activating multiple types of these receptors

receptors also mediate satiety and decreased food consumption

serotonin 5-HT3 receptors

ligand gated ion channels made of combination of 5 subunits

nonselective cation channel. excitatory

targets for a wide variety of therapeutic drugs including one that prevent postoperative nausea and chemotherapy induced vomiting

ATP/Adenosine

all synaptic vesicles contain ATP: co-released with NT

Excitatory NT in motor neurons of spinal cord and ganglia of sensory and autonomic system. also some parts of brain

degraded into adenosine (Non-classic NT)

purines degraded by apyrase and ecto-5’ nucleoside

it is moved back into cells through nuceloside transporter

ATP/Adenosine receptors

3 types of receptors

P2X receptors are ionotropic: nonselective cation channel

one type of metabotropic is more sensitive to ATP(P2Y) while the other is more sensitive to adenosine(A)

metabotropic receptors found throughout the brain and tissues like heart, adipose, and kidney

caffeine blocks adenosine receptors which is believed to cause the stimulant effects

peptide neurotransmitters

some peptide hormones also function as NTs

NTs generated as pre-propetides in ER

goes to Golgi for packaging into vesicles

In vesicles propeptide cleaved into more than one type of neuropeptide

catabolized by peptidases

neuropeptides grouped into 5 categories: brain/gut peptides, opioid, pituitary, hypothalamic releasing hormones, and other peptides

almost all neuropeptide receptors are metabotropic

opioid peptides

discovered in 1970s when looking for endorphins

more than 20 opioid peptides identified that fall into 3 classes: endorphins, enkephalins, and dynorphins

widely distributed in the brain and colocalize with small-molecule NTs

opioids are depressants. Also involved in sexual attraction, and aggressive/submissive behaviors