Neurotransmitters
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Introduction
Neurotransmitters are chemical signals that neurons use to communicate with other neurons and different cells. Most have other uses in the body as well.
Unlike the neuromuscular junction, neuron synapses have more subtle and complex characteristics. Neurotransmitters can stimulate, inhibit, or modulate the postsynaptic neuron.
- acetylcholine
- dopamine
- GABA
- glutamate
- histamine
- norepinephrine
- serotonin
- others
Acetylcholine
Acetylcholine (ACh) is a common neurotransmitter secreted by a variety of neurons.
It binds to two different receptors - Ionotropic (fast) nicotinic receptors and metabotropic (slow) muscarinic receptors.
- role in central nervous system
- role in peripheral nervous system
- receptors and signaling
- agonists and antagonists
- anticholinergic effetcs
- role of acetylcholine in disease
Role in Central Nervous System
Acetylcholine is restricted in the CNS, being limited to:
- basal forebrain complex, innervating hippocampus and all of cortex
- parts of the reticular formation
- pontomesencephalotegmental cholinergic complex - innervates dorsal thalamus and parts of forebrain
- likely involved in arousal, sleep-wake cycles, and perhaps learning and memory
- Alzhemier's diease patients show a significant loss of acetylcholine in the cortex and hippocampus and corresponding loss of cells from the basal nucleus
Role in the Peripheral Nervous System
- Preganglionic neurons of the autonomic nervous system, both the SNS and the PNS, secrete ACh, where its binds to ionotropic nicotinic receptors.
- Postganglionic neurons of the vagus nerve act on metabotropic muscarinic receptors of cardiac cells to reduce heart rate
- Postganglionic PNS neurons secrete ACh at synapses with cardiac and smooth muscle and glands, where it binds to .
- Somatic neurons secrete ACh at the neuro-muscular junction, where it binds nicotinic receptors.
- Some postganglionic SNS neurons express ACh at sweat glands, where it binds muscarinic receptors.
Receptors and Signaling
ACh is made in the pre-synaptic terminal by choline acetyltransferase and is stored and released from vesicles, each which contains 6000-10,000 ACh molecules.
- ionotropic ACh receptors undergo conformational change upon ACh binding, inducing cation influx
- metabotropic receptors activate a-GTP and βγ subunit, which activates K channels, inducing K influx and cell hyperpolarization
ACh is primaily removed form the synapse by the action of acetylcholineesterase (AChE)
Agonists and Antagonists
Agonists
- carbachol (muscarinic)
- succinylcholine binds for prolonged time, leading to secondrary relaxation and flaccid paralysis
- nicotine
AChE inhibitors (reversible)
- donepezil (Aricept) (used in AD)
- neostigmine (used in myesthenia gravis)
AChE inhibitors (irreversible)
- malathion - insecticide
- nerve gas - sarin
Antagonists
- atropine (muscarinic)
- curare (nicotinic)
- benztropine
- botulinum and tetanus toxins inhibit ACh vesicle release
Anticholinergic Effects
anticholinergic effects can cause dry mouth, constipation, blurry vision, delerium, cognitive impairment, etc
- paroxetine is quite strongly anticholinergic
- low potency antipsychotics
Role in Disease
- in myesthenia gravis, antibodies against the AChR form, usually following thymus hyperplasia.
Dopamine
Dopamine is a neurotransmitter important for lots of things. It is also used as a drug.
- role in central nervous system
- role in peripheral nervous system
- receptors and signaling
- role in disease
Role in Central Nervous System
Dopamine is an important neurotransmitter in the CNS. It is involved in the following systems:
- mesolimbic - appears to be involved in psychotic symptoms
- substantia nigra - control of voluntary movement
- ventral tegmental area - reward, drug addiction, schizophrenia
- released from hypothalamus, where it tonically inhibits prolactin secretion from the anterior pituitary
- mesocortical - may have effect on negative symptoms of psychosis
Role in the Peripheral Nervous System
- Dopamine is an important postganglionic sympathetic neurotransmitter acting primarily in renal vascular beds.
- It appears to induce vasodilation at lower doses but vasoconstriction at higher doses.
- It is also likely involved in modulating signals in some ganglia and the ENS.
- activates β1 receptors in the heart, increasing heart rate and contractility
Dopamine Receptors and Signaling
- All DA receptors in the brain are metabotropic, generally causing slow inhibitory action on CNS neurons.
- The D1 receptor is typically associated with adenylate cyclase stimulation and cAMP production, thought to lead to smooth muscle relaxation and vasodilation
- The D2 receptor is thought to inhibit adenylate cyclase, reducing calcium influx and opening potassium channels. It also also appears to inhibit NE release (after binding to pre-synaptic sites?)
Role in Disease
- Dopamine overactivity is associated with schizophrenia
- Loss of dopamine signaling is involved with Parkinson's disease
- Dopamine reward system is involved in most or all cases of drug addiction, with projections leaving the VTA and projecting to the nucleus accumbens.
D2 blockers can
GABA
- role in central nervous system
- role in peripheral nervous system
- receptors and signaling
- agonists and antagonists
- role in disease
Role in Central Nervous System
-
70-80% of CNS neurons use GABA as a neurotransmitter; as such, the brain is largely inhibitory
Role in the Peripheral Nervous System
Receptors and Signaling
- GABA and glycine bind to receptors gating Cl--selective channels, generating IPSPs
GABAA are ionotropic
GABAB are metabotropic, linked via G proteins to opening K channels or suppressing Ca channels
Agonists and Antagonists
Agonists
-
benzodiazepines and barbiturates each bind to an allosteric site on GABAA channels, facilitating Cl- influx
Antagonists
Role in Disease
Glutamate
Glutamate, an amino acid, is the most common excitatory neurotransmitter in the nervous system.
- role in central nervous system
- role in peripheral nervous system
- receptors and signaling
- agonists and antagonists
- role in disease
Role in Central Nervous System
- glutamate and aspartate primarily activate fast, ionotropic cation channels, generating small EPSPs. Many such EPSPs need to sum together to trigger an action potential. The threshold number varies but is roughly in the range of 10-100.
- Glutamate signaling is thought to underly learning and memory
- glutamate overexcitation is also thought to be involved in cell damage and death in Huntington's disease and following acute brain injury, as follows stroke or excessive seizures
Role in the Peripheral Nervous System
Receptors and Signaling
Glutamine is converted to glutamate by glutaminase in the presynaptic cell, stored, and released.
Glutamate can act on four major classes of receptors.
AMPA receptors are ionotropic and are found in most excitatory synapses in the brain. They let Na+, K+, and very little Ca2+.
NMDA receptors, of which there are many, are also ionotropic. During hyperpolarization, NMDA receptors are blocked by magnesium, only opening above - 60 mV. This makes NMDA channels both ligand gated and voltage gated. They co-exist with AMPA-gated channels, opening more slowly once other channels have opened.
kainate receptor channels are a mystery.
mGlu Receptors are metabotropic.
Surrounding glial cells take up glutamate from the synapse, convert in back to glutamine, and return it to pre-synaptic cells.
Agonists and Antagonists
Agonists
Antagonists
Role in Disease
Histamine
- role in central nervous system
- role in peripheral nervous system
- receptors and signaling
- agonists and antagonists
- role in disease
Role in Central Nervous System
Role in the Peripheral Nervous System
Receptors and Signaling
Agonists and Antagonists
Agonists
Antagonists
Role in Disease
Most common excitatory NT
amino acid
every neuron has glutamate receptors
Glutamine is converted to glutamate by glutaminase in the presynaptic cell, stored, and released.
Receptors include AMPA-R, NMDA-R, and MGluR.
NMDA receptors are blocked by magnesium during cell hyperpolarization, and allow Ca influx when the cell is depolarized.
these are thought to underly learning and memory and cell death during stroke.
Surrounding glial cells take up glutamate from the synapse, convert in back to glutamine, and return it to pre-synaptic cells.
Norepinephrine
Norepinephrine (NE) is the primary neurotransmitter of the sympathetic nervous system. Its effects are very similar to those of the hormone epinephrine, released by the adrenal medulla.
Role in the Central Nervous System
NE is used by modulatory system neurons in the locus coeruleus in the reticular activating system to affect arousal, anxiety, etc.
- acts on β-adrenergic receptors on pyramidal cells, with little effect on its own; instead, primes cell for more powerful response to excitatory input such as glutamate
- one way it does so by increasing phosphorylation of K channels, decreasing their opening and increasing the excitability of cells
Effects on the Body
Norepinephrine (NE) is released by most postganglionic cells of the SNS, where it binds to a variety of receptors.
Receptors
| Receptor Locations | Physiological Effects | Intracellular effects | Agonist | Antagonist | |
|---|---|---|---|---|---|
| α1 | smooth muscle cells | peripheral vasoconstriction | increases IP3, DAG, and calcium | phenylephrine | prazosin |
| α2 | presynaptic adrenergic nerve terminals, platelets, lipocytes, SMCs | negative feedback on NE secretion; platelet aggregation | inhibits adenylate cyclase, decreasing cAMP | clonidine | Yohimbine |
| β1 | cardiomyocytes, kidney | stimulates adenylate cyclase, increasing cAMP levels | isoproterenol, dobutamine | atenolol, metoprolol | |
| β2 | lung, intestine | bronciodilation dec. intestinal motility |
albuterol, salbutamol | ||
| β3 |
Agonists
- cocaine - inhibits reuptake
- pseudoephedrine - causes NE release
- phenylephrine - α1 agonist
- salbutamol - β2 agonist
- dobutamine - β1 agonist
Antagonists
- pentolamine - α1 and α2 antagonist
- prazosin - α1 antagonist
- metoprolol - β1 antagonist
Serotonin
Serotonin (5-HT) is a vasoactive amine that acts both as a neurotransmitter and a local signal in inflammation
- role in central nervous system
- role in peripheral nervous system
- receptors and signaling
- role in disease
Role in Central Nervous System
- acts as both an excitatory or inhibitory neurotransmitter
- cell bodies in raphe nuclei in reticular formation in midbrain and pons
- diffuse connections across entire brain
- appear to mediate sleep-wake cycles and different stages of sleep
- implicated in control of mood and emotional behaviour
Role in the Peripheral Nervous System
- produced, stored, and released by platelets following aggregation or stimulation by platelet activating factor
- inflammatory effects similar to histamine, causing arteriole dilation and increasing venule permeability
- produced by enterochromaffin cells in the pancreas
Receptors and Signaling
- many hallucinogenic drugs, such as LSD, appear to interact with serotonergic systems
Role in Disease
- involved in depression, obsessive compulsive disorder
odanestron antagonises emetic signals, used as anti-nausea
Other Neurotransmitters
- opiod peptides
- tachykinins
- endocannabinoids
The four main criteria used to define neurotransmitters are:
- synthesized endogenously
- available in presynaptic neuron in sufficient quantities to exert effect on post-synaptic neuron
- if externally administered, mimics endogenous substance
- mechanism for inactivation exists
Trafficking Neurotransmitters
There are two main fashions of transporting neurotransmitters down the axon.
Slow axonal transport occurs via synthesis in the cell body, are packaged in the golgi, and are then transported down the axon.
Fast transport...
Neurotransmitter Production
In general, decarboxylation activates compunds, while deamination inactivates them.
- Tyrosine is used to synthesize dopamine, norephephrine, and epinephrine, sequentially.
- Histidine is used to synthesize histamine.
- Tryptophan is used to synthesize 5-hydroxy-tryptophan and serotonin.
Resources and References
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