Nervous System Flashcards
communication within the PNS
nerve fibres
sensory reflex arc
synapses
release of NT
2 types of nerve fibres in PNS
afferent - sensory info to CNS
efferent - signals from CNS to periphery
sensory reflex arc pathway
sensory receptors to afferent nerve fibres to dorsal root ganglion with cells bodies of neurones to spinal cord to interneurones (relay) to efferent to effector cell
spinal cord structure
dorsal horn - sensory
lateral horn - spinal preganglionic neurones of ANS
ventral horn - somatic motor neurones
active zone
where vesicles released in synapse
release of NT process
synthesis
storage to protect from enzymes and package at high conc
release - dock, Ca, fusion, exocytosis, endocytosis recycling
activation of ionotropic/G-coupled
inactivation by enzymes by breakdown
somatic NS
voluntary muscle contraction
efferent pathway (motor neurone to skeletal muscle) - single neurone with cell body in ventral horn of spinal cord or nuclei within higher brain centres
1 neurone from spinal cord so can be very long (over 1m)
motor neurone synapses at NMJ/endplate
NT is ACh and choline reabsorbed to presynaptic terminal
autonomic NS
efferent pathway - 2 neurones in series of preganglionic N in brain stem/lateral horn of spinal cord synapses in ganglion (cell bodies) then postganglionic N with cell body in autonomic ganglion outside CNS synpase with effector cells
what NT is released from the preganglionic neurone in both sympathetic and parasympathetic nervous systems?
acetylcholine, ACh
where is NT released from? (structure in NS)
varicosities - swellings on axons which contain vesicles with NT
what NT is used as well as ACh in sympathetic NS?
noradrenaline, NA
released from most postganglionic neurones except sweat glands which use ACh
cholinergic synapses
ACh
2 classes: nAChR (nicotinic), mAChR (muscarinic)
nAChR cholinergic synapses
nicotinic, ligand-gated ion channels, ionotropic
ACh/nicotine activates
5 protein subunits (2a, b, y, d) form channel
bind to alpha to open, M2 transmembrane domain creates channel
like colander not pore
mAChR cholinergic synapses
muscarinic, G-protein coupled, metabotropic
ACh/muscarine/noradrenaline/adrenaline activates
7 transmembrane domains
G protein with aby resting bound to GDP
receptor binds G alpha when activated and GDP replace by GTP so target protein activated
noradrenergic synapses
noradrenaline NT
adrenoceptors (a/b) are G-protein coupled
GPCRs after split
yb of G protein splits with alpha and activates GIRKs (G-protein-gated-inward-rectifier K channel) so open K channel
somatic motor neurones synapses
parasympathetic motor neurone synapses
sympathetic motor neurone synapses
nAChR
nAChR in ganglia and mAChR at effectors
nAChR in ganglia, NA activate and a/b adrenoceptors (nAChR in adrenal medulla causes adrenaline release, nAChR in ganglia causes mAChR in sweat glands)
what receptors are at an NMJ
nAChR - nicotinic acetylcholine receptors
breakdown of ACh
acetate and choline
cholinergic transmission in NMJ
1) SYNTHESIS: choline reuptake Na dependent
precursor choline + acetyl CoA from mitochondria makes choline
acetyltransferase (ChAT) makes ACh
2) STORAGE: active pump H into vesicle by vAChT w/ energy, 2 H out + ACh in
3) RELEASE: blocked by various toxins by blocking Na and Ca channels
4) ACTIVATION: quanta of NT activates nAChR so causes mEPP (miniature end plate potential) which summate and AP so contraction
5) INACTIVATION: AChE acetylcholinesterase breaks ACh
hemicholinium 3
blocks choline reuptake
not used clinically
vesamicol
uptake and storage of ACh in vesicles inhibited
not used clinically
TTX in cholinergic transmission
blocks voltage-gated Na channels so no AP and no release of NT from pufferfish (they get it from sea)
Conatoxins
snails
block P/Q and N-type voltage-gated Ca channels so no NT release
Botulinum toxin in cholinergic transmision
destroys proteins in vesicular fusion like synaptotagmin in lethering vesicle to membrane, so no release
don’t feed children honey because contains toxin from Clostridia Botulinum
Dendrotoxins
block voltage-gated K channels so more Ca influx and too much twitch so paralysis
cone snail venoms
ziconotide
Ca channel blocker given to spinal cord for severe pain relief
black widow spider alpha-Latrotoxin
punch holes in membrane so Ca influx and huge release of NT so spasms and deplete vesicle pool so desensitisation, inhibition of endocytosis and terminal paralysis
types of blockers
block receptors
competitive non-depolarising blockers
irreversible non-depolarising blockers
depolarising blockers
competitive non-depolarising blockers
antagonists, can recover activity with anticholinesterase
Tubocurarine arrow poison causes respiratory paralysis
Vecuronium and Rocuronium act same, prevent movement in surgery
irreversible non-depolarising blockers
alpha-bungarotixin bind where ACh bind but covalently
depolarising blockers (e.g. and phases, clinical)
agonist
Suxamethonium keeps stimulating nAChR
PHASE I: persistent activation of nAChR, prolonged depolarisation, inactivation of Na channels
PHASE II: desensitisation of nAChR, repolarisation of endplate, desensitisation maintains blockade
rapid paralysis for emergency but short duration and side effects
for tracheal intubation to get tube down throat
so don’t contract muscles during electroconvulsive therapy
how is ganglia nAChR different from those at NMJ?
some drugs don’t work on both because subunit composition different
ganglia blockers reduce action of para/sympathetic NS
ganglionic non-depolarising blockers
antagonists
K-bungarotoxin is irreversible like alpha-bungarotoxin at NMJ
trimethaphan is competitive and reduce BP used in surgery
hexamethonium and tubocurarine is non competitive and sits in channel, for hypertension to reducce BP
ganglionic depolarising blockers
agonists
stimulate receptors so inactivate Na and desensitise
nicotine and lobeline agonist for nAChR in ganglionic and chromaffin cells, not used clinically
suxamethonium has NO effect on ganglionic nAChR (only in NMJ)
subtypes of mAChR
M1 - neural, in autonomic ganglia, modulate ganglionic transmission
M2 - cardiac, atria and conducting tissue, cause cardiac slowing and decreased force of contraction
M3 - glandular, salivary glands and smooth muscle of gut, saliva secretion and increased gut motility
M4 - CNS, synaptic transmission
M5 - CNS, substantia nigra, modulate synaptic transmission
ganglionic blockers
inhibits transmission between preganglionic and postganglionic neurons in the Autonomic Nervous System, often by acting as a nicotinic receptor antagonist.
substantia nigra
a basal ganglia structure located in the midbrain that plays an important role in reward and movement
mAChR subtypes are G-protein coupled to different subunits
alpha component of G-protein has diff subtypes
M 1/3/5 coupled to Gaq (queer, odd numbers)
M 2/4 coupled to Gai (inhibitory)
Galphaq
ACh stimulate receptor
receptor stimulation causes Gaq to stimulate PLCb (phospholipase Cbeta) so breaks down PIP2 to DAG + IP3
DAG activates PKC + IP3 so Ca release from internal stores so excitation, secretion, contraction (calcium triggers muscle contraction)
Galphai
ACh stimulate receptor so Gai inhibit adenylate cyclase (AC) so reduced ATP to cAMP conversion so reduced PKA activation and reduced Ca channel activity
Gby also activates K channels so hyperpolarise membrane and slows heart
mAChR agonists
parasympathomimetics - stimulate mACh receptors and stimulate parasympathetic response (sweat glands not paras. but have mAChR)
Pilocarpine - increase secretion in tears saliva sweat, bronchoconstriction, increase mucus production, used for eyedrops
Cevimelin - increase gut motility, relax sphincter, salivation, clinical for dry mouth and eyes
Bethanechol - constrict bladder, relax sphincter, vasodilation, clinical promote gut activity and urinary tract after operation
mAChR antagonists
parasympatholytics - opposes paras. NS
Atropine (like Hercules) - paralyse muscle around pupil, less tears sweat, high temp, less gut motility, less saliva, increased HR, relax bladder, less bronchial secretions
clinical dilate pupil to examine, for diarrhoea, asthma, tremors, motion sickness, anaesthesia
anticholinesterases
inhibit cholinesterases (breakdown of ACh) by attach to active site of enzyme and bond cleaved, bond can be hydrolysed so back to active enzyme
some irreversible so strong bond in catalytic site is resistant to hydrolysis (oximes can reactivate, bind anionic site and try pull off organophosphate from serine so phosphate transferred to oxime, but ageing means longer bond forms more resistant)
alcohol - short duration
carbamate - medium e.g. neostigmine
organophosphate - long, weeks
how is ACh broken down?
active cleft of enzyme has binding site
anionic site binds choline and esteric site binds acetyl
electrostatic attraction keeps ACh in catalytic pocket
cleaves bond so breaks to choline and acetyl
clinical uses of anticholinesterases
neostigmine - reverse NM paralysis, increase ACh
neostigmine and pyridostigmine - longer last, treat myasthenia gravis (MG)
endrophonium - diagnose MG
physostigmine and ecothiopate - treat glaucoma
donepezil, galantamine, rivastigmine - Alzheimer’s, increase ACh
alzheimer’s hypothesis
cholinergic Ns reduced in brain
loss muscarinic receptors and nicotinic receptors
reduced ACh transporters so reduced ACh in brain
myasthenia gravis
autoimmune disease produce Abs to nicotinic receptors
membrane attack complex so invaginations lost on membrane so lat and reduce SA for receptors
cross link Rs so internalise
bind Rs so not respond to ACh
lose NM structure so paralysis
can use anti-AChE so more ACh
organophosphate
nerve agents
G-agents - Tabun pesticide
V-agents - venomous
A-agents - novichoks in attacks
treatment: atrophine reverse excessive ACh vasodilation (affects heart pressure)
oximes reactivate AChE but ageing
valium for seizures
pretreat before with antiAChE
catecholamines
tryptamines
and are all what?
have catechol group
noradrenaline, dopamine, adrenaline hormone
serotonin
monoamines - all have amine group
synthesis and storage of monoamines in noradrenergic transmission
L-tyrosine convert to DOPA (tyrosine hydroxylase adds hydroxyl group) in NA/DA neurones and adrenal chromaffin cells in adrenal medulla
DOPA convert to dopamine (DOPA decarboxylase takes carboxyl group off)
dopamine convert to noradrenaline (dopamine b-hydroxylase in NA vesicles)
noradrenaline to adrenaline (phenylethanolamine N-methyltransferase in chromaffin cells)
release of monoamines in noradrenergic transmission
AP opens Ca channels so Ca in
NT vesicles to presynaptic membrane
2 subtypes of alpha adrenoceptor - a2 on pre sense release of NT (feedback) so inhibits release and switch off Ca channels (inhibitory autoreceptors)
inactivation of noradrenergic transmission
reuptake NA from cleft to pre/post (NET transporter in pre, EMT in post)
MAO and COMT degrade noradrenaline and adrenaline
metabolism of monoamines in noradrenergic transmission
noradrenaline convert to DOMA (monoamine oxidase MAO)
DOMA to UMA
MAO inhibitors
COMT inhibitors
for depression
for Parkinson’s
adrenoceptor diversity
alpha2 inhibits noradrenaline release
more sensitive to NA then adrenaline than isoprenaline (synthetic)
3 beta
more sensitive to isoprenaline than adrenaline than NA
adrenoreceptor actions
alpha1 - contraction in vascular and vas deference smooth muscle
alpha2 - decreases NA release at nerve terminals
beta1 - in cardiac muscle, increase HR and force of contractions
beta2 - cardiac/skeletal muscle blood vessels, bronchial smooth muscle, dilation, relaxation
beta3 - adipose tissue not in brain, lipolysis, breakdown of fat
adrenoceptor signal transduction
alpha 1 is Galphaq coupled so activate PKC and Ca so SM contraction
alpha 2 is Galphai coupled so inhibit adenylate cyclase so less cAMP and less PKA activity and Gyb inhibit Ca channels so less insulin and less NA
beta1/2/3 is Galphas coupled so stimulate adenylate cyclase so more cAMP, more PKA activity, more cardiac output, dilation relaxation, lipolysis
drugs inhibiting synthesis in noradrenergic transmission
a-methylparatyrosine
carbidopa/benserazide
disulfiram
alpha-methylparatyrosine
stops tyrosine conversion to DOPA so decrease NA
for chromaffin cell tumour
carbidopa/benserazide
inhibit DOPA decarboxylase (drug don’t enter brain so only in PNS) so more dopamine but bad side effects on heart/BP
disulfiram (antabuse)
inhibit dopamin-beta-hydroxylase and enzyme for alcohol degradation so bad side effects from alcohol
drugs inhibiting storage in noradrenergic transmission
reserpine
alpha-methyl DOPA
reserpine
inhibit NA uptake so decrease in terminals
decrease sympathetic function
decreased HR/BP but long term damage
alpha-methyl DOPA
alpha-methyl NA instead of NA so activate a2 receptors and less NA so reduced sympathetic NS activity
decrease HR/BP
drugs inhibiting release in dire transmission
bretylium guanethidine
clonidine
bretylium guanethidine
stored in vesicles released by nerve stimulation and block nerve conduction by displacing NA
treat ventricular arrhythmias
clonidine
a2 agonist so decrease NA release so less contraction and treat hypertension, migraines
alpha adrenoceptor antagonists
prazosin (a1) decreases BP
labetalol (a/b) decrease BP via a1
for hypertension
beta adrenoceptor antagonists
propranolol decreases HR/BP/cardiac output via b1, bronchoconstriction (b2)
atenolol decreases HR/BP/cardiac output via b1, for hypertension
pindolol is partial agonist so not full response and inhibit action of full agonist, hypertension
Sympathomimetics
drugs potentiating noradrenergic transmission
mimic or modify the actions of endogenous catecholamines of the sympathetic nervous system. Direct agonists directly activate adrenergic receptors while indirect agonists enhance the actions of endogenous catecholamines
directly acting sympathomimetics
NA (a/b1) increase BP by a1 vasocontriction for shock and cardiac arrest
adrenaline (a/b) increase HR and force, bronchodilation for cardiac arrest, epipen, anaesthesia
salbutamol (b2) smooth muscle contraction (bronchodilation) for asthma and inhibit premature labour
indirectly acting sympathomimetics
tyramine stimulates NA release and competes for NA transporter so increase NA in cleft
dopaminergic receptors
D1-like receptor subtype (D1/5) coupled to Galphas (cAMP and PKA) so voluntary movement and reward
D2-like (D2/3/5) coupled to Galphai (reduce cAMPP and PKA, Gby less Ca and open K) so sleep regulation, mood, attention, hormonal regulation, sympathetic regulation
serotonergic receptors
most G-protein except 5-HT3
5-HT1 coupled to Galphai 5-HT2 coupled to Galphaq 5-HT4 5-HT5 5-HTT 5-HT6 coupled to Galphas
feeding, mood, sleep, sensory pathways, pain, body temp
purines
adenine - purine derivative
adenosine - adenine + ribose
ATP as NT (released when damage), can convert to ADP, AMP, adenosine
adenosine kinase
adenosine conversion to AMP and back
creates inward gradient for adenosine uptake
purinergic receptors
P0 for adenine
P1 for adenosine
P2 for ATP (+other nucleotides)
P2X (1-7 subunits)
P2Y (8 types - 1,2,4,6,11,12,13,14): 2/11 better for ATP, 1/12/13 for ADP, 4/6/14 for UTP/UDP-glucose
P2X ionitropic
P2Y, P0, P1 G-protein coupled
ATP as NT
spontaneous release of ATP from vesicles disappears if desensitise Rs
mediate inhibition and prevent contraction of smooth muscle
purinergic nerves in brain
medial habenula
hippocampus
P2X receptor
trimer forms ion channel with TM2 pointing into it
dolphin topology
fenestrations
ATP stimulates P2X so pain response
A1 agonist induce analgesia
ATP convert to adenosine which stimulate A1 so analgesia
overstimulation of P2X3 receptor cause chronic cough which reduced with antagonist
P2X7 bad in everything like Crohn’s disease, and no desensitisation with ATP
P2Y receptor
G-protein coupled 8 types (1,2,4,6,11,12,13,14) bound by various ligands
1, 2, 4, 6, 11 coupled to Galphaq (PLC-b, glycerol, protein kinase C, release Ca)
11 also coupled to Galphas (stimulate adenylate cyclase)
12 coupled to Galphai/o (inhibitory)
P2Y 1/12 important in aggregation and Clopidogrel AZD targets P2Y12 so treats high platelet aggregation
adenosine (P1) receptors
4 subtypes: A1 (Gai), A2A (Gas), A2B (Gas/q), A3 (Gai)
A1 - reduces tissue activity to reduce ATP usage
adenosine effects
reduce BP
protects heart from heart attack - dilate blood vessels and angiogenesis and inhibit inflammation and slow heart so better adapt and prepared for attack
used for supraventricular tachycardia and convert to sinus normal rhythm
anticonvulsant - dampen electroexcitability of brain and suppress brain activity by ATP metabolised to adenosine, so for epilepsy
antagonist of A1 (CPT) causes seizure activity
iodotubercidin
poison adenosine kinase so can’t convert adenosine to AMP so increase extracellular adenosine by preventing uptake (no inward gradient)
builds and inhibits synaptic transmission by blocking glutamate release from presynaptic
astrocytes in chronic epilepsy (+ treatment)
lots in epileptic tissues in hippocampus (astrogliosis)
Kainate inhibit ADK so elevate adenosine and prevent seizures
receptors for glutamate
both ionotropic (iGluR) and metabotropic (mGluR)
mGluR
metabotropic (GPCR) glutamate receptors
8 subtypes and 3 groups depending on Galpha subunit (q/i/i)
slow
excitatory/inhibitory in CNS
iGluR
ionotropic glutamate receptors
3 subtypes, fast excitation, tetramers (TM1-4 forms pore)
NMDA - GluN1 (obligatory), GluN2A-D, GluN3A/B
AMPA - 4 subunits, GluA1-4, majority of excitation in brain
Kainate - 5 subunits, GluK1-5
NMDAR and AMPAR let Na and Ca in while KAR lets only Na in
glutamatergic synapse
glutamate released and taken up to glial cells where synthesised to glutamine then to glutamate and back to presynaptic neurone
transporter in vesicle creates proton gradient w/ ATPase pump by H into, so H out and glutamate pumps in
clear glutamate by EAAT in presynaptic of glial cells
astrocytes close to synapses regulate activity and release own NT
NMDA
structure: GluN2 (glutamate binding site) and GluN1 (Glycine/D-serine binding site)
Mg blocks because -ve cell potential attracts +ve Mg
no Mg when depolarisation
bad if overactive - brain damage, seizures, stroke
subunit specific - properties depend on subunit composition e.g. 2B open longer, 2D open brief and smaller amplitude, conductance lower in 2D/2C
drugs can target certain compositions to avoid complications with knocking out all receptors
AMPA
majority of excitatory activity in brain, widely distributed
GLUA1/2/3 high density in hippocampus, 4 in cerebellum
regions on receptor can be edited/alternative splice
ligand binding domain, flip/flop region, AP2/NSF binding domain, PD2 binding domain
subunits affect function: QR editing (Q glutamine, R arginine)
non-linear current graph unless GluA2 (R so impermeable to Ca)
how does AMPA receptor change with development?
high Ca permeability early on (8 days)
decrease at 20 days
help shape circuits in brain
AMPAR trafficking
in/out membrane via vesicles/lateral diffusion
varies strength of synaptic transmission
for homeostatic balance
brain not bigger when learn but scaling
differences in NMDA and AMPA transmission
NMDAR responses seen at +50mV while AMPAR activity seen at -70mV at resting potential
active synapses vs silent synapses
active can transmit info at hyperpolarised (resting) because AMPARs while silent lack AMPARs so not transmit at resting because Mg block NMDARs
pairing in NMDA/AMPA
depolarise and continue to stimulate receptor so Mg out and activity seen
difference after pairing - no longer 0 amplitude at resting because Ca in after Mg out NMDA and Ca activates AMPAR so now responds at resting (no new receptors introduced, proved by experiment)
scaling
add AMPA and adjacent synapse reduces by common factor so difference persists
CA1 in hippocampus
damage means unable to form new memories
LTP vs LTD models
long term potentiation vs depression
learning and memory changes synaptic strength, high f stimulation increases amplitude and strength and can be long lasting
low f stimulation response is decreased - LTD
NMDARs in LTP and spatial learning
no LTP means no enhancement from baseline
NMDAR antagonist causes no LTP so response remains the same as before high f stimulation
Morris Water Maze
test hippocampal function of mouse trying to find platform in water
NMDA antagonist causes no learning and equal time spent everywhere
implications of NMDA/AMPA role in synaptic strength
development depends on Ca permeability affects learning/memory, addiction nire GluA1 over time with pain loss of GluA2 and more Ca in stroke LTD synapse loss in Alzheimer's NMDAR antagonist Memantine used in AD
