The neuron: synaptic physiology and NTs week 5 Flashcards
In what 3 ways are NTs inactivated after dissociation from their postsynaptic receptors?
- re-uptake into the pre-synaptic cell
- uptake into glial cells
- enzymatic degradation (such as acetylcholinesterase breaks down ACh into acetate and choline)
T or F: Electrical synapses are not delayed by diffusion of a chemical transmitter across the synaptic cleft and thus are often found where it is important to activate several neurons simultaneously.
True.
While ____ synapses can be either excitatory or inhibitory, _____ synapses are only excitatory.
While chemical synapses can be either excitatory or inhibitory, electrical synapses are only excitatory.
What is the physical basis of an electrical synapse?
What is transmitted at these synapses?
The physical basis of an electrical synapse is the gap junction, a region of apposition of an array of transmembrane proteins (connexons) whose central pores provide continuity between the adjacent cells. In general, small ions such as K+ can pass freely through gap junctions, providing a low resistance electrical connection between the cells. Larger molecules, such as tRNA, can also pass between cells. The conductance of a gap junction can be modified. Calcium ions, pH and transjunctional voltage have been shown to alter the conductance of gap junctions in several systems. Furthermore, a gap junction may be rectifying: current may flow more easily in one direction than in the other.
What is Lambert-Eaton Myasthenic Syndrome (LEMS)?
What kind of disease is LEMS?
What clinical sign/symptom does LEMS cause and why?
What disease is often associated with LEMS?
Blocking calcium influx prevents neurotransmitter release. In the Lambert- Eaton Myasthenic Syndrome (LEMS) presynaptic voltage gated calcium channels at the neuromuscular junction are degraded via an autoimmune mechanism. The autoimmune attack is often based on molecular mimicry between presynaptic voltage gated calcium channels and certain small cell lung cancers. The degradation of the calcium channels prevents influx of calcium and causes weakness. The weakness may be the first clinical sign that leads to the detection of the lung cancer.
What are the effects of botulinum toxin? Where does it act? What is the consequence of this toxin?
What are the effects of the tetanus toxin? Where does it act? What is the consequence of this toxin?
Botulinum toxin preferentially interferes with vesicle docking and neurotransmitter (Ach) (interferes with SNARE vesicle docking proteins) release at the neuromuscular junction producing decreased muscle activity (flaccid paralysis/weakness).
Tetanus toxin cleaves synaptobrevin/VAMP blocking vesicle docking and release of inhibitory neurotransmitters (GABA/glycine) in the spinal cord and brainstem (CNS) resulting in markedly increased muscle activity (spastic paralysis), such as lockjaw and is often fatal. We are immunized against tetanus early in life to protect against this.
What are the 3 fundamental classes of NTs? (just list)
- small molecule
- large molecule
- gasses
Where in neurons are small molecule NT’s synthesized? Large molecule NT’s?
What controls NT synthesis?
What is the mainstay treatment of Parkinson’s disease and how does it work (generally)?
Small molecule transmitters are synthesized in the presynaptic terminal. Larger neurotransmitters (peptides) are synthesized in the cell body and transported to the terminal. The availability of precursors controls neurotransmitter synthesis. In Parkinson’s disease (PD) there is degeneration of dopamine producing neurons resulting in motor impairment. Administration of L-dopa, a dopamine precursor, increases the dopamine synthesized by the surviving neurons and is a mainstay of treatment of PD.
Name examples of small molecule NTs.
For small molecule NTs, what type of synaptic vesicles are excitatory NTs usually packaged in? Inhibitory?
In what concentration range do small molecule NTs act in?
How are small molecule NTs rid of after acting on the presynaptic receptors?
What are their molecular weights?
Small Molecule Neurotransmitters (e.g., Acetylcholine (ACh) or Dopamine (DA)).
- They are synthesized at the site of release.
- They are packaged in small synaptic vesicles: round vesicles usually contain excitatory neurotransmitters and flattened vesicles inhibitory transmitters
- They act in the low micromolar range.
- They are taken back up by the terminal from which they were released by a high affinity re-uptake pump that involves a facilitated diffusion protein (shuttle protein) OR they are catabolized by specific enzymes located in the synapse OR they can be taken up by glial cells for catabolism via a low affinity facilitated diffusion protein.
- They have short diffusion distances due to catabolism and re-uptake.
- Their molecular weights are in the 100s.
Name examples of large molecule NTs.
How do large molecule NTs get to axon terminals?
In what concentration range do these NTs act?
What happens to large molecule NTs after acting at the postsynaptic neuron?
What are their molecular weights?
What may large molecule NTs be co-released with? What is often required for release of large molecule NTs?
Large Molecule Neurotransmitters (neuropeptides; e.g., enkephalins (Enk), endorphins, substance P (Sub P)).
- They are synthesized in the nucleus and packaged by the Golgi apparatus into large, dense core vesicles and transported to the nerve terminal.
- They act in the pico- and nanomolar range.
- They are not taken back up by the terminal, the empty vesicle is recycled back up to the cell body.
- They are catabolized by non-specific peptidases located in extracellular space.
- They have short diffusion distances.
- They have molecular weights in the 1,000 -10,000.
- They may be released at the same axon terminal, as cotransmitters, with a small molecule neurotransmitter, but often require repetitive, or higher frequency action potentials. If there is too much NT release, releasing neuropeptides may decrease excitability of postsynaptic neuron-form of regulation.
Attached pic: A. Single action potentials (1) lead to calcium influx (2) and release of small molecule neurotransmitters from small synaptic vesicles (3) in the presynaptic terminal. Repetitive action potentials (1) cause greater calcium influx (2) and co-release of both small neurotransmitter (3) and neuropeptide neurotransmitter (4).
Name examples of gas NTs.
Where are gas NTs synthesized?
How are they released? Where in the postsynaptic cell do they act?
What happens to gas NTs after acting on their targets?
Gas Neurotransmitters (e.g., nitric oxide (NO) or carbon monoxide (CO)).
- They are synthesized locally near their release site.
- They are not packaged in vesicles, but rather synthesized and immediately diffuse to their targets due to high lipid solubility.
- Can work on intercellular targets instead of traditional receptors.
- Are not catabolized per se, but rather diffuse away or are oxidized to an inactive state.
What are neuromodulators?
What kind of molecules are neuromodulators?
What are neuromodulators often co-localized with?
Where can they act?
The action of neurotransmitters is affected by Neuromodulators.
A: A catch-all category of molecules that are not responsible for direct neuron-neuron communication (as is true of the neurotransmitters), but rather modifies the action of neurotransmitters.
B: Neuromodulation can be mediated by neuropeptides and other non-peptide molecules (glucocorticoids or estrogens) that can, for example, affect a receptor protein’s affinity for a small molecule neurotransmitter.
i. Neuropeptides are often co-localized with small molecule neurotransmitters where two different vesicular pools exist.
ii. Neuropeptides can be co-localized with small molecule neurotransmitters where they are found within the same vesicular pool.
iii. They can act at a local synapse, have a more regional or field effect (paracrine effects), or act over distances (hormone).
iv. Their actions can even reverse the primary effect of the released neurotransmitter (from inhibition to excitation).
How long do the effects of NTs that act on ionotropic receptors generally last?
Neurotransmitters that act through ionotropic receptors generally produce rapid effects that are temporary and rapidly reversible. The duration of the effect of the neurotransmitter is dictated by its half-life in the synapse and terminated by being taken back up or by catabolism.
Generally, what effect do metabotropic receptors have on cells?
After ligand binding, what do metabotropic receptors do?
Generally, how long do the effects from metabotropic receptors last?
Metabotropic receptors gain their name from the fact that they act by inducing a metabolic action in the target cell. This is a G-protein coupled mechanism that leads to an increase in cAMP, a decrease in cAMP, or some other second messenger activity.
- Metabotropic receptors may also open up ion channels and therefore possess ionotropic effects as well.
- Other second messenger systems include cGMP, activation of the Phospholipase A2, arachidonic acid pathways, and the diacyl-glycerol (DAG)/inositol triphosphate (IP3) pathway.
- The metabolic consequences of metabotropic receptor activation can have long-term and profound effects on the function of a neuron or glial cell.
a. Alterations in the phosphorylation status of a target cell through metabotropic actions can regulate cell function (e.g., alterations in the phosphorylation status of proteins involved with neurotransmitter release can, as a result of autoreceptor activation, be phosphorylated or dephosphorylated to influence transmitter storage). These second messengers can even bind to the receptor and decrease its response to the neurotransmitter (desensitization). Alternatively, second messengers can increase future response to neurotransmitters (sensitization).
b. Neurotransmitters can alter immediate early genes which translocate into the nucleus and subsequently enhance the synthesis of new AMPA receptors as occurs as part of long-term potentiation (LTP) following high level Glu release.
c. Regulation of trophic factors which alter the physical structure of the CNS (e.g., chronic treatment with a DA agonist can downregulate striatal production of target-derived trophic factors leading to “pruning” of presynaptic terminals; alternatively chronic administration of an antagonist increases target-derived trophic factor production leading to sprouting).
d. Production of gases such as NO and CO which, in turn, can influence the production of retrograde neurotransmitters (e.g., NO released by target neuron diffuses back into presynaptic terminal to increase future Glu release as part of long term potentiation, LTP).
What NT is the primary excitatory NT in the CNS?
glutamate
What other receptors can glutamate bind to? (just list)
AMPA
Kainate
metabotropic receptors
What change to GABA-A receptors does binding of barbituates induce?
What effects do barbituates have? (why is it diagnosed?)
Barbiturates can open the channel independent of the presence of GABA. When they bind to the barbiturate site, they increase the duration of time the channel is open. They can produce global depression of the CNS, but unlike the benzodiazepines, can literally shut down the CNS invoking fatal respiratory depression. The barbiturates include powerful anesthetics and anticonvulsants.
Describe spatial and temporal summation.
Spatial summation is the additive effect produced by many EPSPs or IPSPs that have been generated at many different synapses on the same postsynaptic neuron at the same time.
Temporal summation of EPSPs or IPSPs is the additive effect produced by many EPSPs or IPSPs that have been generated at the same synapse by a series of high-frequency action potentials on the presynaptic neuron.
