Disorders of Membrane Excitation Flashcards
electrical signals play key roles in control functions when what is needed..?(2)
speed and propagation
e.g. cardiac and muscle contraction, insulin secretion, signaling in the brain, spinal cord, peripheral motor neurons
electrical functions are affected in acquired and hereditary diseases which involve ion channel proteins… lots of them
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what is an example of disorders of resting K channels?
Type II diabetes of infancy
resting k+ channel in pancreatic beta cell - helps release insulin… does make insulin just can’t release it
Type II Diabetes of Infancy is really rare!! It is 1-5% of diabetes in young people
Due to Katp channel defect
Often misdiagnosed
Most are spontaneous mutation - spermatogenesis problem
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What is the pancreas?
Endocrine organ that is nestled between the liver and the intestine!
Regulates blood glucose etc
Type II diabetes of infancy have a mutation in what gene?
what does it prevent?
the gene encoding the SUR subunit of the Katp channel
it prevents the channel from closing in response to elevated ATP
what do children of type II diabetes of infancy not respond to?
what type of drug do they respond to?
insulin!
sulfonylurea drugs - drug targets the SUR subunit and causes the channel to CLOSE!
What is the Katp (resting K+ channel) channel a sensor of?
What does it control?
What binds to it to close it?
glucose sensor
controls insulin secretion in beta cells
ATP closes the pore (ligand gated - binds from the inside)
Give the mechanism of insulin secretion:
Glucose enters beta cells via Glut2 transporters
metabolism of glucose increases the ATP/ADP ratio
ATP binds to the KATP channel, causing it to close
K channel closing depolarizes the membrane
Depolarization opens voltage-dependent Ca2+ channels, Ca2+ influx follows
Increased intracellular Ca2+ leads to fusion of secretory vesicles, insulin release
For a NORMAL functioning B cell the Katp channel is what at rest?
open at rest!
it is allowing K+efflux, maintaining a negative RMP
K+ channel closing in pancreatic beta cel depolarizes the membrane and triggers….
repetitive action potentials!!!
there is a slow depolarization followed by bursting APs!!!
at low glucose…
Katp open, Ca2+ closed, low ATP
at high glucose…
Katp close, Ca2+ open, high ATP
insulin secreted
Ca2+ channels require a greater depolarization threshold than Na+
How can Ca2+ fire in bursts?
They do not have the property of fast/slow inactivation
Beta cells in the pancreas use slow changes in RMP to trigger insulin secretion
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RMP depolarizes when the PNa/PK ratio is..
higher!
Katp acts as a sensor for plasma glucose and as a switch to turn insulin secretion on/off
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in absence of glucose, beta cells have a stable RMP near..
-60mV
neonatal diabetes = type II diabetes of infancy
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Give the structure of the Katp channel
8 subunit protein:
4 pore forming subunits (Kir6.2) - binds ATP!
4 reg subunits (SUR1)
- regulates channel activity - target of sulfonylurea drugs (hint the name)
What is SUR?
unique ATP-binding cassette protein that functions as an ion channel regulator
In neonatal diabetes, the channel loses its gating by ATP, stays OPEN! - no insulin secretion
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Kir6.2 (KCNJ11) mutations
Most common is R201H (Arg to His)
Decreases ability of ATP to bind
SUR1 (ABCC8) mutations
Increase ability of Mg2+ ADP to bind, which inhibits channel gating by ATP binding
What is the most common mutation resulting in neonatal diabetes?
substitution for Arg to His at aa 201 in the Kir6.2 subunit
This decreases the ability of ATP to bind and the channel remains open…. idk if this is important….
What are some Katp drugs?
Diazoxide and Sulfonylureas bind to the SUR subunit; close the channel
Sulfyonylureas also alleviate symptoms due to mutated Katp channels in extrapancreatic tissues
What is an example of disorders of action potential generation?
myotonia congenita
what is myotonia congenita (MC)?
disease of action potential generation in skeletal muscle from an abnormal CI channel
pts have difficulty relaxing their skeletal muscles
syndrome of abnormal membrane excitability
experience additional contraptions of their muscles following a voluntary (Willed) effort
the extra contractions occur because the muscle membrane is firing extra action potentials in response to input from the motor nerve
Skeletal muscle normally has a high permeability to what ion…
chloride
Skeletal muscle has two channels to help depolarize it…. they are?
voltage gated potassium channel and a chloride channel
What does the EMG show in MC pts?
dive bomber response
EMG records AP activity in skeletal muscle
Muscle fibers from unaffected individuals fire a single action potential and then become refractory.
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muscle fibers from individuals with MC fire action potentials repetitively in a high-frequency pattern which continues for some time
This extra contraction can produce stiffness which hinders movement. Myotonic individuals have difficulty relaxing the voluntary muscles in a normal manner
***see pp that has for normal and then MC action potentials!
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What is slower in myotonia?
repolarization!
if slower, the Na+ have time to reset, then they retire because the membrane is still above threshold
skeletal muscle depolarization:
recall that Cl- moves into the cell and K+ moves out; both make the inner membrane surface negative
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Skeletal muscles have a large safety factor in the number of Na channels, and it is possible to trigger a second action potential if only a few percent have reset to the closed state. In MC, the extra action potentials continue to excite the muscles to contract, preventing the patient from relaxing the voluntary muscles in a normal manner.
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What is the structure of the Cl- channel?
Mutation in MC?
12 membrane spanning helices - assemble to form a central pore
mutation in MC results from a gly changing to a glutamate at aa 230 (or opposite)
disorders of AP propagation?
multiple schlerosis - a demyelinating disorder
