Peripheral Nerve Transmission L1 Flashcards
whats the ENS?
enteric nervous system (ENS) - gut wall - is also considered to be a part of the ANS.
where do parasympathetic ganglion lie?
close to or on the target organ
For the somatic nervous system, the neurotransmitter _______ is released from the endings of the motor neurons (myelinated __ fibres) that innervate skeletal muscle at the neuromuscular junctions (NMJs)
For the somatic nervous system, the neurotransmitter (acetylcholine, ACh) is released from the endings of the motor neurons (myelinated A- fibres) that innervate skeletal muscle at the neuromuscular junctions (NMJs
does the adrenal medulla behave as a modified sympathetic ganglion?
yep - hence only one nerve innervating it
nerves that synpase onthe adrenal gland release what?
ACh
is the adernal medulla effectively a modified adrenal medulla?
yep
how do sympathetic post ganglionic neurones interact with their target orgnas?
nerves do not form highly defined structures like the NMJ of skeletal muscle fibres,
rather they have bulbous expansions, or varicosities, that are distributed along their axons within their target organ.
T or F
often more tha one transmitter is released from the neuroeffector junction
T
pharmacological agents can influence the _____, the -______ and the _______ of these endogenous transmitters
pharmacological agents can influence the release, the life time and the functions of these endogenous transmitters
all non-peptide transmitters are synthesized locally where?
all non-peptide transmitters are synthesized locally within the nerve terminal
where do the enzymes for neurotransmitter synthesis come from?
the necessary enzymes are brought to the nerve terminus from the cell body by the slow axonal transport
describe the syntehsis of neuropeptides
neuropeptides (often initially as much larger pre-propeptides) are synthesized in the soma where they are also packaged into LArge dense core vesicles (see later) within which further posttranslational processing take place .
Peptide-filled vesicles are then transported along an axon to the nerve terminal via the fast axonal transport.
2 types of vesicel?
two types of vesicles
- small, clear-core
- large, dense-cor
clear-core vesicles are clustered at the ….
clear-core vesicles are clustered at the active zone
describe the synpatic vesicel cycle
T or F
all neurotransmitters (small molecules and peptides) are loaded into vesicles soon after their synthesis
almost true
exceptions include gaseous transmitters - NO, CO, H2S ect
Depolarisation of the nerve terminal by the action potential triggers opening of voltage-gated Ca2+ channels (Cav2 series: mainly __ and _ type) through which Ca2+ enters into the pre-synaptic terminal
Depolarisation of the nerve terminal by the action potential triggers opening of voltage-gated Ca2+ channels (Cav2 series: mainly P/Q and N-type) through which Ca2+ enters into the pre-synaptic terminal
do Cavs also cluster at the active zone?
yes
are docked vesicles only a small proportion of the totla releasable pool ?
yes. theres also a reserve pool tethered to the cytoskeleton
what are synapsins
present on the surface of the synaptic vesicles
→ link vesicles to the cytoskeleton
→ process regulated by phosphorylation
when synapsins are not phosphorylated - are the vesuicles bound or free?
non-phosphorylated = bound to vesiclesand actin
describe transmitter loading into vesicels
- loaded by ATP driven mechanism.
- proton pump acidifis vesicle interior
- creates electrochemical gradient
- Transmitter loaded utilising this gradient
how does the depolarisation of the neurone lead to the dissociation of bound vesicels from the cytoskeleton>
• activation (depolarisation) of neurons
→ Ca2+ enters cells through voltage-gated Ca2+ channels (Cavs)
→ synapsins become phosphorylated by CaMKII
→ vesicles become freed from synapsins and move to active zone
whats the molecule which phosphorylates synasins?
Ca2+/calmodulin-dependent protein kinase, type II (CaMKII) which phosphorylates synapsins
is vesicle priming ATP dependant?
yes
what protein (in vesicle exocytosis) is involved in Calcium sensing?
synaptotagmins
desribe empty vesicle endocytosis
vesicles first get coated by clathrin and later shed the coat and recycle to the interior of the synaptic nerve terminal.
The empty vesicles either refill immediately with transmitter to resume the cycle or pass through the endosomal sorting.
a number of congenital myasthenic syndromes arise from ….
, a number of congenital myasthenic syndromes arise from defects in ACh release due to inadequate number of synaptic vesicles available for release
describe familial infantile myasthenia
there is no shortage of vesicles but they are much smaller in size
Describe Lambert-Eaton myasthenic syndrome (LEMS),
ACh release is reduced, primarily due to autoimmune destruction of neuronal Cav channels present in the active zone.
2 classes of SNARe proteins
t and v
t = target membrane
v = vesicel membrane
v SNARe example?
synaptobrevin
2 T SNARES
SNAP-25
syntaxin
. During exocytosis, the SNAREs form a core ‘trans-SNARE’ complex which consists of ….
. During exocytosis, the SNAREs form a core ‘trans-SNARE’ complex which consists of 4 alpha helices - one each from synaptobrevin and syntaxin and two from SNAP-25.
Many other proteins that notably include Munc 13, Munc 18, complexins, Rab3A etc. are also involved in the process.
how arew SNARE complexes dissociated?
a cytoplasmic ATPase called NSF (N-ethylmaleimide-sensitive fusion protein) binds to SNARE complexes via an adaptor protein called SNAP.
NSF and SNAP use the energy of ATP hydrolysis to dissociate SNARE complexes, thereby regenerating free SNAREs.
which toxins target SNAREs
Certain neurotoxins, such as botulinum toxins (BoTxs) and tetanus toxin (TeNT) are known to cleave SNAREs selectively, thereby inhibiting synaptic vesicle exocytosis
which SNARE does tetanus toxin cleave?
synaptobrevin
which SNARE do botox B, D, F and G cleave?
synaptobrevin
which SNARE do BOtox A and E cleave?
SNAP-25
which SNARe does botox C1 cleave?
Syntaxin and SNAP-25
2 ways transmitter is removed from the cleft?
- uptake via transporter
- degraded by an enzyme
describe how pre-synaptic modulation can modulate transmitter release
wher is choline obtained from?
mainly the diet
but also from reuptake from the cleft
Ach is hydrolysed to what?
choline and acetate
what tendas to be rate limiting in ACh synthesis.
Under many circumstances, this reuptake and availability of choline can be rate limiting in ACh synthesis.
describe how choline is retaken up into the nerve terminal end
a high affinity choline transporter (ChT1, a member of the solute carrier family of proteins) that also transports Na+
what chemical inhibits the uptake of Choline>
hemicholinium
what enzyme produces ACh
Within the cytoplasm of the pre-synaptic nerves, choline is acetylated to form ACh by choline acetyltransferase (ChAT or CAT).
in Ach synthesis - where does the acetate come from
The acetyl group comes from Acetyl Coenzyme A originating from the mitochondria.
regarding ACh syntehsis - which common false transmitter is often produced?
- Triethylcholine competes with choline as a substrate of CAT and gets converted to acetyltriethylcholine which then is released in place of ACh.
Acetyltriethylcholine is far less potent than ACh at cholinergic receptors and acts as a false neurotransmitter.
describe direwctly acting pharmacological agents
physically interacts with & activates/inhibits/influences the postsynaptic receptors
eg: agonist, antagonist, allosteric modulator or a pore blocker (if the target is an ion channel)
descrieb indirectly acting pharmacological agents?
reduces/enhances the amount of the endogenous transmitter available for binding to the post synaptic receptors
• themselves do not bind to the postsynaptic target receptors
how is ACh loaded into vesicels?
after synthesis, ACh is loaded into cholinergic vesicles by a vesicular ACh transporter (VAChT).
The energy needed for this process is provided by the high H+ gradient prevailing across the vesicular membrane (maintained by a V-type ATPase.).
This allows the VAChT to exchange H+ for ACh.
vesicles that store ACh are typically ____-core and also contain ____ at a ratio of 10:1
vesicles that store ACh are typically clear-core and also contain ATP at a ratio of 10:1
Some cholinergic nerves also contain dense-core vesicles containing a neuropeptide called …….
Some cholinergic nerves also contain dense-core vesicles containing a neuropeptide called the vasoactive intestinal peptide (VIP).
Both ATP and VIP function as a __________ at some synapses (see later section on NANC transmission).
Both ATP and VIP function as a co-transmitters at some synapses (see later section on NANC transmission).
_______ – an experimental compound, is a non-competitive and reversible blocker of VAChT.
vesamicol – an experimental compound, is a non-competitive and reversible blocker of VAChT.
Btoox toxins are produced from?
Clostridium botulinum – a Gram-positive bacterium
where do Botoxs preferentially targeT?
and why?
the peripheral terminals of the motor neurons releasing ACh at the NMJs. \
Their heavy chains bind to some gangliosides specific to the target nerves which allow them to be endocytosed specifically into these nerves.
signs of Botulism?
symptoms of botulism include skeletal muscle weakness (which may lead to respiratory paralysis) as well as some autonomic signs that would be associated with loss of cholinergic activity (e.g. constipation, blurred vision, dry mouth, difficulty in swallowing, urinary retention etc.).
what does vesamicol do?
vesamicol inhibits VAChT reversibly & noncompetitively
β-bungarotoxin (β-BuTx) - how does it owkr?
inhibits ACh release but through a different but poorly-understood mechanism
causes irreversible structural damage to the pre-synaptic nerve terminal -> probably via its PLA2 activity which degrades the active zone phospholipids
α-latrotoxin (α-LTX) - how does it wrk
triggers massive ACh release even in absence of nerve stimulation -> leads to respiratory failure in affected animal
leads to depletion of ACh
that as a tetramer, this toxin can form a Ca2+- permeable ion channel.
describe how Tetanus neurotoxin (TeNT) work
cleaves synaptobrevin & thus impairs glycine release from inhibitory interneurons in the spinal cord → motor neurons become disinhibited → unabated ACh release -> tetanic contractions
enters NS throguh NMJ - moves to CNS in endosome - discharged into intersynaptic space - binds inhibitory neurones
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