Review Phys Flashcards
what promotes hyperkalemia?
deficiency in insulin or aldosterone
cell death
hyperkalemia = increased ECF K+ –> decreased K+ efflux out of the cells (membrane potential becomes less negative, because less is moving out, thus depolarized)
hypokalemia
decreased ECF K+ –> more inctracellular K+ rushing out (increased efflux)
–> membrane potential becoming more negative = hyperpolarized
increased K+ conductance
results in increased K+ efflux from cell –> membrane becomes more negative = hyperpolarized
what does resting potential depend on
VERY sensitive to changes in ECF K+ !!!!
tetrodotoxin
- eating puffer fish (diet hx necessary for ddx)
- numbness of hands and feet, mm. weakness, respiratory problems,
- no proven antidote; charcoal binds toxin
MOA:
- TTX blocks voltage-gated sodium channels resulting in depolarization being inhibited and AP generation/propogation is inhibited
lambert-eaton
sx: proximal weakness and absent DTRs: mm. response increases w/ repeated activation
- Lambert-Eaton Myasthenic Syndrome (LEMS) = paraneoplastic syndrome
MOA:
- pre-synaptic AI attack directed against voltage-gated calcium channels on the PRESYNAPTIC motor nerve terminal
- calcium normally promotes ACh vesicle fusion and exocytosis and is registered by synaptogamin
repeated stimulation results in increased mm. strength b/c stimulation can increase Ca2+ influx through functioning channels –> increased release in ACh
malignant hyperthermia
- sx: increase body temperature, mm. rigidity, tachypnea, tachycardia, elevated PCO2 following anesthesia
- heritable condition (AD)
MOA:
- disorder of Ca2+ regulation in skeletal mm. triggered by volatile anesthetics
- causes uncontrolled release of Ca2+ from SR –> rigidity, tachycardia, hyperventolation, hyperthermia
- acute hyper-metabolic state w/in mm. tissue; prolonged contraction
affected receptor?
- defect in RYR1 gene or DHPR
botulism
- targets the synaptic vesicle fusion process
- clostridium botulinum: peripheral effects, flaccid paralysis, inhibition of ACh release at the NMJ
sx: canned food, dry mouth, double vision, difficulty swallowing, vomiting, diarrhea
tx: botulin antitoxin
myasthenia gravis
- sx: present with thyroid problems, difficulty reading, diplopia and blurred vision, mm. weakness, speech swallowing (bulbar mm.), neck mm, proximal limb weakness
- weakness worsens with increased activity, improves with rest
MOA: autoimmune disease - resulting from circulating Abs directed against nAChR (causing destruction) = fewer channels capable of opening in response to ACh
- normal release of ACh has little effect due to fewer channels capable of opening in response to Ach
= decreased ability to generate an end-plate potential
test? temporary improvement after Ice pack test: cooling inhibits AChE activity
tx: AChE inhibitor
tetanus
- TT targets synaptobrevin: synaptic vesicle fusion
- neurotoxin of clostridium tetani
sx: c/o jaw pain, inability to fulloy open mouth, difficulty swallowing, generalized stiffness, stepped on a nail
spastic paralysis: d/t central effects results in inhibition of the inhibitory interneurons
tx: anti-tetanus immunoglobulin
steps of synaptic transmission
AP at axon terminal of presynaptic neuron opens voltage-gated Ca2+ channels
Ca2+ influx from ECF into synaptic knob
Ca2+ influx induces fusion & exocytosis of synaptic vesicles → neurotransmitter into the synaptic cleft
N.T.s diffuse & bind to receptors on subsynaptic membrane of the postsynaptic neuron
Bound N.T.s result in alteration of membrane permeability of postsynaptic neuron
Termination of signal by removal of N.T. from synaptic cleft (enzymatic breakdown, cellular uptake, diffusion)
active zone
Dense spots over which synaptic vesicles are clustered; where fusion of synaptic vesicles & release of ACh occurs
Oriented directly over secondary postsynaptic clefts between adjacent postjunctional folds
Postjunctional Folds = Extensive invaginations on postsynaptic membrane directly undernerve terminal
- Increase surface area of muscle plasma membrane
AChE
terminates synaptic transmission after AP –> choline and acetate
Choline acetyltransferase
Synthesizes ACh from choline + acetyl coenzyme A
ACh-H+ exchanger
ACh uptake by synaptic vesicle
Driven by vesicular proton electrochemical gradient (ACh influx coupled with H+ efflux; due to positive voltage & low pH inside)
What forms anchor?
Synaptobrevin (v-snare) + SNAP- 25 + syntaxin (presynaptic t-snares)
- helps drive vesicle fusion
what is Ca2+ receptor of synaptic vesicle?
synaptogamin
Detects rise in [Ca2+]i and triggers exocytosis of docked vesicles
tetanus target?
synaptobrevin
botluinum B, D, F, G target?
synaptobrevin
botulinum A/E target?
cleaves SNAP-25
botulinum C target?
cleaves syntaxin
ACh receptor
equally permeable to Na and K+
when ACh binds results in great increase in Na+ causing the membrane potential to become positive
end-plate potential = graded potential of end plate
local current flows and opens voltage gated Na+ channels in adjacent membrrane
resultant Na2_ entry reduces the potential to threshold causing an AP to be propogated throughout mm. fiber
A band
Myosin (thick) filaments; Partial overlap with actin (thin) filaments
H zone
Middle of A band; Part of myosin where actin does not overlap
M line
Extends vertically down center of A band
I band:
Part of actin not overlapping myosin; no project into A band
Z line
Thin filament attachment
thick filament
bipolar assembly of multiple myosin molecules:
2 important binding sites:
- actin binding site
- Myosin ATPase site - for binding and hydrolyzing ATP
Actin
- backbone is thin filament
(13 individual actin make one single filament strand) - associated with 2 regulatory protein:
1. tropomyosin: blocks the myosin binding site at rest
2. troponin: - Troponin T: binds single tropomyosin molecule
- Troponin C: binds Ca2+
- Troponin I: binds actin and inhibits contraction
When Ca2+ combines with troponin, tropomyosin slips away from its blocking position between actin and myosin
With the exposure of the myosin-binding site on actin, a cross bridge is formed and muscle contraction can occur
excitation contraction coupling
- Action potential of sarcolemma (excitation) –> Increased [Ca2+]i allowing actin & myosin binding (coupling) –> Power stroke:
↑ [Ca2+]i = intracellular signal to trigger & sustain contraction (skeletal, cardiac, & smooth muscle)
Key link between excitation and contraction
Action potentials propagate from the sarcolemma to the interior of muscle fibers via transverse tubules
Ca2+ released from the sarcoplasmic reticulum
Ca2+ binds troponin, allows for cross-bridge formation
SR triad?
sarcoplasmic reticulum cisterna surround the transverse tubule (T-tubule)
- AP is propogated through T tubule causing calcium release from lateral sacs of the SR
- Two important channels:
1. dihydropyridine receptor (L-type ca2+ channel) DHP: voltage gated channel located within the T-tubule, when depolarizes mechanically activates RYR
2. ryanodine receptor (RYR): calcium release channel: releases Ca2+ from SR
relaxation
= an active process that requires reuptake of Ca2+ from sarcoplasm back into the SR
- If unregulated, cross-bridge cycle would continue until myocyte is depleted of ATP
- After an AP, Ca2+ must be removed from the cytoplasm for contraction to cease and for relaxation to occur
- When Ca2+ levels decrease, troponin and tropomyosin move back in place and cover myosin-binding site on actin
ATP required for:
- Ca2+ pumps
- ATPase binding site on myosin head (new ATP must be bound for cross-bridge to be broken)
pumps that remove Ca2+ for relaxation
- Na+- Ca2+ Exchanger and Ca2+ Pump
(cell ) - minor mechanism for calcium removal - SERCA: Sarcoplasmic and Endoplasmic Reticulum Ca2+-ATPase type pump
- Ca2+ re-uptake into the SR
Most important mechanism for returning [Ca2+]i to resting levels in skeletal m.
NOTE: calcium bindings proteins are in SR:
- High [Ca2+] in the SR inhibits activity of SERCA
- Ca2+-binding proteins in the SR lumen can delay inhibition of Ca2+ pump activity
- Ca2+-binding proteins buffer increased [Ca2+] during Ca2+ re-uptake and can increase Ca2+ storage capacity of the SR
- calsequestrin = major Ca2+ binding protein in skeletal mm.
- localized in SR at triad jn
- forms complex with RYR, facilitates mm. relaxation by buffering Ca2+
cross-bridge cycle
- ATP binds to myosin head causing dissociation of actin myosin complex
- ATP is hydrolyzed, causing myosin heads to return to their resting conformation
- a cross-bridge forms and the myosin head binds to new position on actin
- P- is released, myosin heads change conformation resulting in power stroke
- ADP is released and Myosin and Actin are in teh attached state
NOTE: increased ca2+ = increased cross-bridge formation = directly proportional to tension production
dendrodotoxin
from mamba snakes
blocks the voltage gated K+ channels, effectively inhibiting repolarization
- results in prolonged AP, prolonged Ca2+ influx at nerve terminal –> enchanced ACh release –> hyperexcitability and convulsive sx
myasthenia gravis and the eyes
90% of patients with MG develop ophthalmologic manifestations
2 clinical forms:
- only ocular sx: ocular MG
- general MG: generalized weakness (85% of pts. progress to this)
Proposed reasons for impact on eyes:
- Ocular weakness may be more noticeable in patients
- Perhaps due to fewer ACh receptors in eye muscles (less prominent synaptic folds compared to limb muscles)
- High rate of firing frequency of ocular motor neurons may contribute to neuromuscular transmission fatigue
- Lower quantal release of ACh vesicles per synaptic event in ocular motor neurons
conotoxin
venom of marine cone snail
blocks N-type voltage gated Ca2+ channels –> analgesic effect
