MSK physiology review (Montemayor) Flashcards
hyperkalemia effects on membrane potential
depolarizes neurons
ECF K affects membrane excitablity. What hormones effect cellular uptake of K +
insulin
epinephrine
aldosterone
deficiencies in these may cause hyperkalemia
Resting membrane potential is very sensitive to changes in ECF K+
with increased K+ conductance (K+ efflux) what happens
hyperpolarized membrane (becomes more negative)
what happens in hypokalemia (Decreased ECF K+)
increased K+ efflux - hyperpolarized
what happens with increased ECF K+ (hyperkalemia)
a decrease in K+ efflux (or promotes K+ influx)
membrane becomes less negative, depolarized
what is the NMJ?
specialized synapse b/w motor neuron and skeletal muscle fiber
what are some differences b/w a synapse and the NMJ?
- synapse is b/w two neurons. NMJ is b/w a motor neuron and skeletal muscle
- one-to-one transmission of action potentials occurs at the NMJ wherease one AP in a presynaptic neuron cannot by itself bring about an AP in post-synpatic neuron and requires summation of EPSP’s
- NMJ is ALWAYS excitatory (an EPP)
- synapse is either excitatory or inhibitory
-inhibition of skeletal muscles cannot occur at the NMJ- can only occur in the CNS through IPSP’s at dendrites and cell body of the motor neuron
what is the role of acetylcholinesterase
terminates synapatic transmission after AP
hydrolyzes ACh to choline and acetate
where is the site of ACh synthesis
Nerve terminal
how is ACh made
Choline acetyltransferase synthesizes ACh from choline + acetyl CoA
how does ACh uptake occur into synpatic vesicles
By the ACH-H+ exchanger
Driven by vesicular proton electrochemical gradient
(ACh influx coupled with H+ efflux; due to positive voltage & low pH inside)
what is synaptobrevin, where is it located, what does it form complexes with ?
V-SNARE
this is on the vesicle membrane
essential for transmitter release
Forms complex with SNAP-25 & syntaxin (presynaptic membrane proteins; t-SNAREs)
Helps drive vesicle fusion
synaptotagmin
Ca2+ receptor on the vesicle membrane
synaptotagmin detects rise in Ca intracellular and triggers exocytosis of docked vesicles
Ca2+ enters through voltage-gated Ca2+ channels near the active zone of the presynaptic membrane
Triggers vesicle fusion and exocytosis
target of tetanus (endoproteinase)
synaptobrevin
botulinum B, D, F, G target (these are endoproteinases)
synaptobrevin
Botulinum A/E target
cleave SNAP-25 (pre-synaptic protein)
Botulinum C1 target
cleaves Syntaxin (pre-synaptic protein)
what is the ACh receptor permeable to
cations (Na , K, Ca)
NOT anions
the function of ACh receptor is to raise Vm above threshold (-50 mV –> action potential)
what is the end plate potential and what occurs after this takes place?
graded potential of the end plate, small depolarization
as the ACHr channel at the muscle end plate opens, Na and K become equally permeable and the result is an increase in the normally low resting permeabilty of Na relative to K
large movement of Na goes into the muscle cell compared to a smaller movement of K+ outward
local current flow opens voltage gated Na 2+ channels in the adjacent membrane
the resultant Na2+ entry reduces the potential to threshold initiating an AP, which is propagated throughout the muscle fiber
A band
Myosin (thick) filaments; Partial overlap with actin (thin) filaments
H zone
middle of the A band
part of where actin does not overlap
M line
extends vertically down center of A band (myosin thick filaments)
I band
part of actin not overlapping with myosin
no project into A band
Z line
thin filament attachment
what is the thick filament
what are its components
bipolar assembly of multiple myosin molecules
2 myosin heavy chains (MHC) 3 regions: Rod-(tail) alpha helices Hinge (arm) Head- form cross bridges, binding actin on thin filament
4 light chains
- 2 alkali (essential)
- 2 regulatory light chains
what are the two binding sites on the myosin heavy chain head
actin binding site (for cross bridge formation)
myosin ATPase site (for binding and hydrolyzing ATP)
how many actin monomers form 1 helical turn on single strand of filamentous actin
13
the thin filament (F-actin) is associated with what 2 important regulatory actin-binding proteins
tropomysin
troponin
actin (thin filaments) have what important binding site
myosin binding site
blocked by tropomyosin at rest
what makes up tropomysin
2 alpha helices coiled around eachother
regulates binding of myosin heads to myosin binding site on actin
troponin T
TnT
binds to single tropomysin molecule
troponin C
binds Ca2+
Troponin I
binds to actin and inhibits contraction
what is excitation contraction coupling ?
Action potential of sarcolemma (excitation) –> Increased [Ca2+]i allowing actin & myosin binding (coupling) –> Power stroke
an increase in Ca intracellularly is a signal to trigger and sustain a contraction (key link b/w excitation and contraction)
AP’s propagate from the sarcolemma to the interior of muscle fibers via transverse tubules
Ca released from SR
Ca binds to troponin allowing cross bridge formation
what makes up the triad in skeletal muscle and why is this structure significant ?
T tubule and 2 associated cisternae (specialized regions of SR)
Crucial role in linking excitation to contraction
Propagation of AP into T tubules depolarizes triad
Results in Ca2+ release from lateral sacs of the sarcoplasmic reticulum
Two important channels
1. Dihydropyridine receptor
2. Ryanodine receptor
where do the t tubules penetrate the muscle cell
A and I bands
DHP (dihydropyridine receptor)
L type voltage gated Ca2+ channels (role is voltage sensor)
associated with T -tubule membrane
they are in clusters of 4
Conformational changes in 4 L-type Ca2+ channels → induces a conformational change in 4 subunits of the Ca2+-release channel
Ryanodine (RyR) receptor
Ca2+ release Channel
Role: releases stored Ca from the SR
associated with the SR membrane
cluster at the portion of the SR membrane opposite the t tubule
what are the steps in EC coupling in skeletal muscle (involving the triad)
Depolarization of voltage-sensor L-type Ca2+ channel (Dihydropyridine) on the T-tubule membrane
Mechanical activation of Ca2+-release channel (Ryanodine) in the SR
Ca2+ stored in the SR rapidly leaves through the Ca2+-release channel
what is necessary for relaxation of muscle to take place
requires reuptake of Ca from sarcoplasm back into SR.
if unregulated, cross bridge cycling 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
relaxation is an active process
ATP is required!! for :
Ca pumps
ATPase binding site on myosin head (New atp must be bound for cross-bridge to be broken)
what are the pumps which remove Ca for relaxation
Na-Ca exchanger and Ca2+ pump
- MINOR
- Na in, Ca out
- Ca out- H+ in
Sarcoplasmic and Endoplasmic Reticulum Ca2+- ATPase (SERCA) type Ca2+ pump
- Ca2+ reuptake into the SR
- Ca into SR, H+ out into muscle cytosol
- MOST IMPORTANT
what is the role of Ca2+ binding proteins in the SR
- Calsequestrin
- Calreticulin- binding protein in smooth muscle
High [Ca2+] in the SR inhibits activity of SERCA (impacts gradient)
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
Ca2+ -binding proteins may have as many as 50 binding sites per molecule
Calsequestrin
Major Ca2+-binding protein in skeletal muscle
Localized in SR at triad junction
Forms complex with Ca2+-release channel (RYR)
Facilitates muscle relaxation by buffering Ca2+ AND unbinds Ca2+ near Ca2+-release channel
Tetrodotoxin
inside puffer fish
give activated charcoal to bind toxin if ingested
blocks Na channels - depolarization is inhibited
saxitoxin
in shellfish
blocks Na channels
lidocaine, procaine, tetracaine-
block nerve impulse generation and propagation by inhibiting voltage-gated Na channels
these are local anesthetics
what is malignant hyperthermia
rare, heritable condition
(auto dominant) that can be triggered by volatile anesthetics and some muscle relaxers
block nerve impulse generation and propagation by inhibiting voltage-gated Na channels
What is the cause?
Disorder of Ca2+ regulation in skeletal muscle triggered by volatile anesthetics & some muscle relaxers
Uncontrolled release of Ca2+ from the SR → rigidity, tachycardia, hyperventilation, and hyperthermia
Acute hyper-metabolic state within muscle tissue; prolonged contraction
which receptor is effected in malignant hyperthermia
RYR located on the SR membrane
defect in the RYR1 gene for the ryanodine receptor (Ca2+ release channel)
myasthenia gravis
Autoimmune: circulating antibodies directed against nAChR are commonly detected
Immune-mediated destruction or impaired binding of nicotinic ACh receptors
Fewer channels capable of opening in response to ACh: ↓ ability to generate an end-plate potential
weakness and fatigue worsen with increased activity
Neural conduction and sensory and autonomic responses are normal
extraocular m.m. are initially affected (ptosis, diplopia, blurred vision) [small motor units]
Bulbar muscles (speech and swallowing)
Neck muscles
Proximal limb muscles
why do ice packs work in myasthenia gravis
cooling slows or inhibits AChE activity
what is Lambert-Eaton Myasthenic Syndrome (LEMS)
paraneoplastic syndrome
Circulating antibodies directed against voltage-gated Ca2+ channels are detected on the pre-synaptic motor nerve terminal
pt’s show proximal weakness and absent tendon reflexes
EMG initially shows a low-amplitude muscle response which significantly increases following repeated activation
a PRE-synaptic disease
synaptotagmin
Ca2+ sensor on the vesicle
Why does repetitive stimulation result in increased contractile strength in this patient with Lambert-Eaton vs. decreased strength after repetitive use in the patient with Myasthenia gravis?
Rapid, repetitive stimulation can increase Ca2+ influx via functioning channels
Increase release of ACh
Presynaptic stores of ACh and postsynaptic AChR are intact the EPP will raise the membrane above threshold and permit generation of muscle AP
what is the effect of omega - conotoxin
venom of marine coil snake
Blocks N-type voltage-gated Ca2+ channels (on the presynaptic membrane)
Analgesic effect
Other forms of conotoxin block: nicotinic ACh receptors, K+ channels, voltage-gated Na+ channels (activation & inactivation)
clostridium botulinum
peripheral effects
flaccid paralylsis
inhibition of ACh release at the NMJ
With a similar molecular mechanism of action (effect on synaptobrevin), how do you explain the spastic paralysis resulting from tetanus toxin?
Central effects
Binds NMJ presynaptic membrane, retroaxonally transported to SC
NT release is blocked
Impact spinal inhibitory interneurons
