Exam 2: Neurotransmitters hoe Flashcards
Small molecule neurotransmitter synthesis and transport:
- Synthesis occurs locally within axon terminals
- The enzymes needed to synthesize the neurotransmitters are sent from the cell body to the axon terminals by slow axonal transport
- The neurotransmitter is then loaded into vesicles at the terminal—the vesicles are visually clear (i.e. small clear-core vesicles
Peptide synthesis and transport:
- Synthesis occurs in the cell body
- The peptide is put in to vesicles and sent from the cell body to the axon terminals by fast axonal transport
- The vesicles get to the axon terminal and then are released once the signal is sent
Monoamines
The monoamines dopamine (DA), norepinephrine (NE) and serotonin (5HT) are heavily implicated in addiction, drugs of abuse and therapeutic drugs
Dopamine and Norepinephrine Percursor and Enzymes
- tyrosine
- tyrosine hydroxylase (TH)
- aromatic amino acid decarboxylase (AADC)
- Tyrosine is converted to DOPA by TH and DOPA is then converted to dopamine by AADC
Storage of DA and NE
- After synthesis, catecholamines are packaged into vesicles
- A specific transporter in the vesicle membrane recognizes monoamines – the vesicular monoamine transporter (VMAT)
Release of DA and NE: VMAT Blockage
- VMAT can be blocked by the drug reserpine, which is used to treat high blood pressure. Blocking VMAT prevents synaptic vesicles filling, which decreases neurotransmitter release
Release of DA and NE
- Catecholamine release is inhibited by autoreceptors on neuron cell bodies, terminals, and dendrites.
- The autoreceptors enhance the opening voltage-gated K+ channels. This shortens the duration of action potentials and reduces the Ca2+ influx and, thus, vesicles exocytosis.
2 major forms of Inactivation for DA and NE
Enzymatic and Reuptake
Inactivation for DA and NE: Enzymatic
- Enzymatic : two major catecholamine enzymatic inactivators: catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO).
- MAO inhibitors are used to treat depression
- COMT inhibitors are given with Parkinson’s disease treatments to increase their effectiveness
Inactivation for DA and NE: Reuptake
- Transporter-There are two types of catecholamine transporters: dopamine transporter (DAT) and norepinephrine transporter (NET)
- Psychostimulants, such as cocaine and amphetamines, block catecholamine transporters—this increases synaptic catecholamine levels
- Antidepressants also work, in part, by blocking norepinephrine reuptake
Receptors for DA
- DA uses five receptor subtypes, D1 to D5.
- All are metabotrophic : they interact with G proteins and function via second messengers.
- Nearly all current antischizophrenic drugs are D2 receptor antagonists.
- Generally excitatory receptors
Receptors for NE
- NE receptors are also metabotropic
- Psychoactive drugs targeting NE often involve working memory, such as clonidine.
Function of DA
Dopamine signaling plays a role in reward-based learning and motor control
Function of NE
Norepinephrine plays a role in arousal, cognition, emotion, attention and memory
Function of 5HT
Serotonin is involved in learning and memory, anxiety, and other emotional behaviors.
DA Neural Circuits
- Nigrostriatal pathway: substantia nigari to the striatum. Function is for voluntary movement, and neurons in this circuit are lost in Parkinson’s disease
- Mesolimbic pathway: ventral tegmental area to the limbic system. Function is for reward and addiction
- Mesocortical pathway : ventral tegmental area to the prefrontal cortex. Function is for motivation and emotional responses
NE Neural Circuits
- The locus coeruleus (LC) in the pons contains a dense collection of NE neuronal cell bodies. These neurons project widely to all areas of the cerebral cortex, cerebellum and spinal cord
- Drugs that target NE have broad effects, from the CNS to the PNS
Serotonin Precursor and Enzymes
- tryptophan
- Tryptophan is converted to serotonin in two steps involving two enzymes: tryptophan hydroxylase (TPH) and AADC
Serotonin Storage and Release
- VMAT is responsible for loading serotonin in to vesicles
- Autoreceptors on axon terminals regulate release and synthesis of serotonin
- MDMA (aka ecstasy) stimulates 5HT release
Serotonin Inactivation
- Reuptake: serotonin reuptake transporter (SERT) is target of SSRIs in depression. Cocaine also blocks SERT.
- Enzymatic degradation: monoamine oxidase (MAO)
Serotonin Receptors
- Most 5HT receptors are metabotropic and generally have inhibitory functions, but some are excitatory as well
- Hallucigenic drugs often target 5HT, for example LSD stimulates a 5HT receptor
- Newer drugs to treat schizophrenia also target and block 5HT receptors (clozapine and Risperdal)
Serotonin Neural Circuits
- Almost all serotonergic neurons in the CNS are found along the midline of the brainstem, associated with the raphe nuclei.
- They project widely to areas in the cerebral cortex, including the hippocampus and amygdala
Acetylcholine Precursor and Enzymes
- acetyl CoA and choline
- From the precursors acetyl CoA (made from glucose) and choline. The enzyme choline acetyltransferase (ChAT)
Acetylcholine Storage
Once ACh is made, ACh is put into vesicles by vesicular Ach transporter (VAChT)
Acetylcholine Release
1) Vesicles then release the acetylcholine at the membrane
2) Botulism toxin inhibits ACh release. Inhibition of cholinergic activity can be deadly because of muscular paralysis
3) Black widow spider venom causes massive release of ACh in the PNS. Overactivity of the cholinergic system causes muscle pain, tremors, nausea,
Acetylcholine Termination (1-3)
1) Termination of Ach at the synaptic cleft is done by the enzyme acetylcholineeasterase (AChE)
2) AChE is concentrated in the synaptic cleft, where neurotransmitter release is occurring
3) AChE degrades the neurotransmitter so it can no longer bind to postsynaptic receptors
-The AChE breaks down
acetylcholine back down to
choline, which gets taken
back up by the neuron to be
used again to make ACh
Acetylcholine Termination (4-5)
4) Some compounds cause irreversible inhibition of AChE. Weak versions are used as insecticides.
5) Very toxic varieties are “nerve gases,” Sarin and Soman. ACh accumulation and overstimulation of cholinergic synapses throughout both the CNS and PNS lead to muscle paralysis and death by asphyxiation
Acetylcholine Receptors
- nicotinic acetylcholine receptors (nAChRs, ligand gated ion channels) and
- muscarinic acetylcholine receptors (mAChrs, ligand gated metabotropic receptors)
Acetylcholine Receptors Nicotinic
- Nicotinic receptors are fast excitatory receptors present in both the PNS and CNS
- Bungarotoxin is derived from snake venom and blocks muscle nAChRs but not neuronal nAChRs
Acetylcholine Receptors Muscarinic
Muscarinic receptors are in the CNS and PNS and contribute to reward and dependence-producing effects of abused drugs
Acetylcholine Neural Circuits
1) In the brain, cholinergic cell bodies are clustered in only a few areas.
2) The basal forebrain cholinergic system (BFCS): neurons are in several brain areas
a. BFCS is the origin of cholinergic innervation of the cerebral cortex, hippocampus, and other limbic system structures.
Glutamate Function
A. Glutamate is an extremely important excitatory neurotransmitter in the brain-broad functions, not one specific role
B. Glutamate can also be highly toxic to neurons if there is overexcitation of glutamate-containing neurons
1) In times of neuronal stress, neurons often release excessive glutamate which can lead to cell death (i.e. epilepsy, stroke, etc.)
Glutamate Precursor and enzymes
1) Glutamine is the precursor to glutamate and glutamine is taken into the presynaptic terminal by the system A transporter 2 (SAT2)
2) The enzyme glutaminase converts the glutamine to glutamate in the presynaptic membrane cytoplasm
Glutamate Storage
Vesicular glutamate transporters (VGLUT)load the vesicles with glutamate and the vesicle is now ready for release
Glutamate Termination
- Glutamate signaling is terminated from the presynaptic side by excitatory amino acid transporters (EAATS).
- EAATs are present on glial cells as well. The glutamate is taken up via the EAATs in the glial cells and turned back into glutamine.
- The glial cells then send glutamine back out, where neurons can take it back up to make more glutamate
- Thus the termination and production of glutamate are intertwined
Glutamate Receptors: Ionotropic
- AMPA, Kainate and NMDA receptors (Ionotropic)
- The ionotropic glutamate receptors all produce EPSPs and are non selective cation channels like the nACHRs, meaning they let multiple ions through the pore (Na and K)
Glutamate Receptors: Metabotropic
- Metabotropic receptors (mGluR) are widely distributed throughout the brain. They can be inhibitory or excitatory
- They participate in locomotor activity, motor coordination, cognition, mood, and pain perception.
- mGluR drugs are being developed for treatment of many neuropsychiatric disorders.
Acetylcholine Function
Acetylcholine (ACh) is present at the neuromuscular junction for voluntary muscle control, in the visceral motor system (i.e. autonomic nervous system) and within the central nervous system
Gaba Function
The major inhibitory amino acid transmitters are GABA (γ-aminobutyric acid) and glycine. Inhibitory transmission is just as important as excitatory; if either GABA or glycine are blocked, convulsions and death can result
Gaba Precursor and Enzymes
- Glutamate is the predominant precursor for GABA. The enzyme glutamic acid decarboxylase (GAD) converts glutamate to GABA
- GAD requires a co-factor, a molecule derived from vitamin B6, to function. In the early 1950s some infant formulas did not have vitamin B6, which caused a GABA deficiency in a small number of infants, in some cases this was fatal.
Gaba Storage
GABA is loaded to synaptic vesicles via a vesicular GABA transporters (VGAT)
Gaba Termination
- GABA signaling is terminated via GAT transporters on glia and neurons
- Drugs that treat epilepsy can inhibit GAT transporters, which reduce neuronal excitation
Gaba Receptors
- GABA has metabotropic and ionotropic receptors-both types allow chloride to flow in the cell, producing an IPSP
- Benzodiazepines and barbiturates involve enhancing GABA receptor function
Gaba Neural Circuits
In the cortex and hippocampus, GABA is found in many local interneurons. Also found in neurons that project to other regions
Excitotoxicity & why it is clinically
????
Monoamine Theory of Depression
The monoamine theory of depression states that the symptoms of clinical depression are caused by loss of transmission at the monoamine synapses in the brain (i.e. decreased monoamines)
Diagnose & Treat Depression using just neurotransmitters
1) Monoamine oxidase inhibitors (MAOIs). MAOIs block activity of monoamine oxidase, allowing for more monoamine to be available
2) Tricyclic antidepressants
Block monoamine clearance from the synapse, so more monoamines are available in the synaptic cleft to signal with
3) Selective serotonin reuptake inhibitors (SSRIs) – Zoloft, Prozac, paxil; Block clearance of a serotonin from the synapse
What features make nitric oxide (NO) an unusual neurotransmitter?
- They are not stored in neurons, not released by vesicular fusion, do not have clear termination processes, and do not bind to specific receptors on the postsynaptic membrane—basically gaseous neurotransmitters violate every rule for what make a neurotransmitter
- NO also does not bind receptors but instead acts on secondary messenger systems in the postsynaptic neuron
What are the 3 categories of neurotransmitters?
1) Cell-impermeant – these molecules bind to the extracellular side of receptors. Most neurotransmitters fall under this category.
2) Cell-permeant – these molecules go into the cell after release and act on intracellular receptors. Steroids and thyroid hormones fall under this category.
3) Cell-associated -no molecule is released, instead a molecule on one cell binds to a receptor on another cell. Integrins and neural adhesion molecules are examples
4 types of receptors
1) Channel-linked (ion channels)
2) Enzyme-linked
3) G-protein coupled
4) Intracellular
Ion Channels
- Are also referred to as ligand-gated ion channels
- Binding of the transmitter molecule on the extracellular side causes the ion channel to change confirmation and allow the flow of ions
- Many of the neurotransmitters we discussed in the previous lectures acted on ligand-gated ion channels
- These response are fast in comparison to g-protein coupled receptors
Enzyme-linked receptors
- Binding of transmitter molecule on the extracellular side of the enzyme
- Binding causes the enzyme to perform its catalytic function, which often involves phosphorylating target molecules
- Example of enzyme-linked receptors are protein kinases – the function of kinases is to phosphorylate targets
G protein-coupled receptors
- A signaling molecule binds to the extracellular side of this receptor, which causes a cascade of intracellular signals to occur
- GTP-binding proteins are what dissociate in response to transmitter binding
- Many neurotransmitters act on GPCRs: acetylcholine, norepinephrine, ATP etc.
Intracellular receptors
- Intracellular binding of a signaling molecule activated this type of receptor
- Generally, these types of receptors when activated modify the transcription/translational pathways in some way
- Example is the nuclear receptor
What are the Gs/Gq in relation to GPCR signaling?
- Neurotransmitters that bind g-protein receptors act on heterotrimeric g-proteins
- There are 3 distinct g-protein subunits: α,β, and γ
- The Gα unit has three different subtypes, each of which activates different secondary messengers—Gs, Gq and Gi
What are the key kinases involved in GPCR signaling?
Gs - protein kinase A (PKA)
Gq - protein kinase C (PKC)
