17_Synaptic Transmission 1_Q and A_Jonathan Flashcards
What are gap junction channels in the NS made of?
a connexon, is built from six identical subunits called connexins.
Are connexons pure gap junctions or can they be regulated?
Functionally, connexon permeability can be regulated by second messengers, pH and Ca2+. For example, Ca2+ “uncouple” electrically-coupled neurons by blocking connexons. This may prevent high concentrations of Ca2+ that arise as a given cell dies from traversing into coupled cells and promoting their demise.
Are mutations in connexins associated with any illnesses?
There are a number of central nervous system (CNS) diseases associated with genes encoding gap junction channel proteins. ex: congenital deafness.
Congenital deafness can be characterized as…
recessive,
nonsyndromic (restricted to the inner ear) deafness,
progressive dominant deafness,
syndromic (associated with other symptoms, especially skin diseases) deafness.
Mutations in specific connexin genes have been associated with all of these forms.
What is the significance of Connexin 26 in deafness?
mutations in the gene encoding connexin 26 are believed to account for ~50% of cases of inherited non-syndromic deafness.
What is the general mechanism involved in non-syndrome deafness and connexons?
Gap junctions expressed in the support cells of the Organ of Corti are involved in maintaining [K+] in the three chambers: The scala tympani and scala vestibuli have perilymph (ionic composition like CSF), and the scala media has endolymph (which has a high K+).
long-lasting changes in Vrest»_space; disruption of ionic homeostasis looses hair cells
Additionally, the loss of gap junction function compromises the passage of important signaling molecules, such as cAMP and IP3, which permeate Cx26-containing connexons (disruption of metabolic homeostasis). Disruption of both processes may contribute to the death of support cells and subsequent death of inner and/or outer hair cells.
What are the basics of chemical transmission of nerve cells?
- Neurotransmitter is stored in presynaptic vesicles
- Exocytosis of presynaptic vesicles requires influx of Ca2+ ions
upon depolarization - Specific cognate receptors for each neurotransmitter are
expressed in the postsynaptic membrane - Neurotransmitter release and opening of the postsynaptic
receptors is very fast: ~500 µsec from the time an action
potential invades the nerve terminal until current starts to
flow through the postsynaptic receptor (synaptic delay). - A variety of mechanism exists for terminating the action of
these substances.
What are the two classes of neurotransmitters based on size?
- Small molecules:
Biogenic amines (dopamine, norepinephrine, epinephrine, 5-HT, histamine),
glutamate, γ-aminobutyric acid (GABA), glycine, and acetylcholine (ACh) - Larger and neurohormones
Over 100 identified, and list still expanding, For example, opioids, cannabinoids, substance P, vasopressin, oxytocin, gonadotropin releasing hormone (GnRH), neuropeptide Y, and many more.
What are the two major classes of neurotransmitter receptors based on function?
Ionotropic
Metabotropic
neurotransmitters in and of themselves are neither excitatory nor inhibitory. Rather it is the interaction of a given neurotransmitter with a specific partnering receptor that determines inhibition versus excitation.
Neurotransmitters in and of themselves are neither excitatory nor inhibitory. Rather it is the interaction of a given neurotransmitter with a specific partnering receptor that determines inhibition versus excitation.
What are excitatory neurotransmitters?
Nicotinic acetylcholine receptors skeletal muscle ACh receptors neuronal ACh receptors Glutamate receptors NMDA AMPA Kainate 5-HT3 class of serotonin receptors (a minor class of the serotonin receptors) 5-HT: 5-hydroxytryptamine or serotonin Purinergic (adenosine and ATP) receptors
What are Inhibitory receptors (when activated by partnering ligand)
γ-Aminobutyric acid (GABA) type A receptors (also type C; not as prevalent). GABA interacting with GABAA receptors provides the major mechanism for generating fast inhibition (usually by hyperpolarization) in the adult brain. Early in development, GABA interacting with GABAA receptors depolarizes neurons. This is not due to any difference in the receptor itself or in GABA, but to a developmental shift in the intracellular concentration of [chloride], which is the major permeant ion through the GABAA receptor.
Glycine receptors. Glycine binding to glycine receptors also promotes fast inhibition. This type of receptor predominates in the spinal cord.
Sample list of Metabotropic Neurotransmitter Receptors (G Protein-Coupled):
α and β norepinephrine (NE) receptors serotonin (5-HT1,2,4,5,6,7) receptors dopamine (DA) receptors muscarinic ACh receptors GABAB receptors L-AP4 glutamate receptors ACPD (metabotropic) glutamate receptors Cannabinoid receptors (CB1,2) Well over 50 receptors for neuromodulatory peptides ATP and adenosine
**The definition of excitation is that the action of the neurotransmitter is to drive the membrane potential (Vm) towards a value that is MORE DEPOLARIZED than the threshold potential for generating an action potential (Vthreshold) *****
**The definition of inhibition is that the action of the neurotransmitter KEEPS Vm from reaching Vthreshold*****
**The definition of excitation is that the action of the neurotransmitter is to drive the membrane potential (Vm) towards a value that is MORE DEPOLARIZED than the threshold potential for generating an action potential (Vthreshold) *****
**The definition of inhibition is that the action of the neurotransmitter KEEPS Vm from reaching Vthreshold*****
Just like ACh, which can activate both ionotropic (nicotinic) receptors and metabotropic (muscarinic) receptors, GABA, glutamate, serotonin, and ATP can also activate both ionotropic and metabotropic receptors. Release of a single neurotransmitter from a presynaptic axon terminal, therefore, can give rise to a multiplicity of postsynaptic effects that may vary in whether they promote excitation or inhibition in the target cell and in how long they last.
Just like ACh, which can activate both ionotropic (nicotinic) receptors and metabotropic (muscarinic) receptors, GABA, glutamate, serotonin, and ATP can also activate both ionotropic and metabotropic receptors. Release of a single neurotransmitter from a presynaptic axon terminal, therefore, can give rise to a multiplicity of postsynaptic effects that may vary in whether they promote excitation or inhibition in the target cell and in how long they last.
What is an Active Zone?
On the presynaptic side, the synaptic machinery is organized into structures called active zones.
ex: neurotransmitter plus vessicles, SNARES, Ca Dependent Channel
What are SNAREs on the pre-synaptic vesicles?
What are SNARES on the presynaptic membrane?
Vessicles:
1. Synaptotagmin
(Ca2+ sensor)
2. Synaptobrevin
Membrane
- SNAP 25
- Syntaxin
Explain SNARE fusion.
In brief, the two SNARE proteins in the plasma membrane (SNAP-25 and syntaxin 1) and the vesicle membrane SNARE (synaptobrevin) cycle through an assembly/disassembly cycle that requires energy provided by NSF (NSF is a membrane fusion protein aka an AAA + - ATPase). When these molecules come into contact with one another, they undergo a conformational change in which α-helices from the different molecules orient in parallel and “zipper” together (from the trans to the cis ends). This conformational zippering releases a large amount of energy, which, in turn feeds the fusion of the vesicle and presynaptic membranes.
