Calcium in cellular function Flashcards
How is low calcium conc in the cel regulated? (3 ways)
- regulated ca entry
- regulated ca efflux
- regulated exchange between cytosol and stores
what are 4 routes of ca entry into cell?
- voltage gated calcium channels (VGCCs)
- ligand gated calcium channels (LGCCs)
- store-operated calcium channels (SOCCs)
- Na/Ca exchange
where are DHP CCBs located?
vascular/smooth tissue
where are non-DHP CCBs located?
cardiac tissue
Which channel do ω-conotoxins, such as ziconotide act on and how do they work?
N type VGCCs
prevent Ca entry into the presynaptic nerve terminal
inhibits ACh release
pain transmission inhibited
Verapamil moa?
- blocks Ltype VGCCs
- prevents influx of Ca2+
- prevents contractions
- depresses electrical activity in heart
nifedipine moa?
- blocks L-type VGCCs
- prevents ca influx into smooth muscle cell during depolarisation
Therapeutic effects of nifedipine?
- relaxes blood vessels (hypotensive)
- increases the supply of blood and oxygen to the heart while reducing its workload (antianginal)
What therapeutic effects does verapamil exert?
- relaxes blood vessels (hypotensive)
- increases the supply of blood and oxygen to the heart while reducing its workload (antianginal)
side effects of nifedepine?
dizziness
lightheadedness
reflex tachycardia - if BP decreases, the heart beats faster to raise it
side effects of verapamil?
abdo pain, dizziness, nausea, peripheral oedema
What is the only true LGC receptor in smooth muscle cell and what activayes it?
P2X receptor, activcated by ATP
How does excess Ca lead to excitotoxicity?
- NMDA Glutamate receptor has ↑Ca2+ permeability
- ↑ Ca2+ influx
- excess Ca2+ causes overactivation of NMDA receptor
- induces Ca-dependent proteases to induce apoptosis - EXCITOTOXICITY
- cell death
under what conditions do store-operate calcium channels (SOCs) allow ca entry?
when intracellular ca stores are depleted
they are NOT sensitive to intracellular ca conc
How does ca enter cells via SOCs?
- when intracellular ca conc is low
- STIM is recruited from ER and plasma membrane
- this activates ORAI1
- this allows ca entry from extracellular areas into cell
what is calcium extrusion?
- calcium actively pumped outwards across CSM
- ca pumped inwards from cytosol to ER/SR
How does Na/Ca exchanger (NCX) work?
- pumps 3 Na into cell, 1 Ca out of cell - causing DEPOLARISATION
- produces electrochemical Na conc gradient
- this energy allows countertransport of Ca
- Ca accumulates intracellularly
How do cardiac glycosides work and therapeutic effect?
therapeutic effect: increase contractile force of heart
moa:
inhibit Na/K pump
increased [Na]i slows Ca extrusion via NCX
raised [Na]i drive Ca extrusion into SR so the amount of Ca increased with each AP
this increases contractility of heart
indications of digoxin
- HF, Afib
What 3 factors determine intracellular calcium conc?
- Ca2+ entry
- Ca2+ extrusion
- Ca2+ exchange
Where does Ca2+ extrusion occur?
out of CSM
inwards across ER/SR
What does Ca2+ extrusion rely on?
ATP
which pump is responsible for maintaining the resting membrane potential?
Na/K ATPase pump
Which ion has the greatest impact on the resting membrane potential?
Potassium
WHy does K has the greatest effect on RP?
K+ moves out of cells
Na+ and Cl- move into cell
At resting state, cell is permeable to K+; this exerts the greatest influence on the resting membrane potential out of the three ions
What causes refractory periods?
inactivation gate of the Na+ channel
Once inactivated, the Na+ channel cannot respond to another stimulus until the gates are reset
Give an example of a drug that acts on an ion channel. How does it work?
DHP CCB: amlodipine acts on voltage-dependent L type ca channel → inhibits Ca influx in vascular smooth cells and myocardial cells → decreased peripheral vascular resistance
What factors increase the excitability of a cell?
- no of Na/Ca channels
- reduced AP threshold
What factors decrease the excitability of a cell?
- increases in resting K conductance
what does length of the refractory period determine?
determines the AP frequency
How do use-dependent drugs work?
Type I antiarrhythmic drugs block the cardiac sodium channel in a use-dependent fashion.
This use-dependent behavior causes increased drug binding and consequently increased sodium channel blockade at faster stimulation rates.
Which calcium channel is involved in smooth muscle contraction?
LGCC called P2X receptor
what is absolute Refractory period?
time where 2nd AP CANNOT be initiated despite magnitude of a stimulus
what is relative Refractory period?
time where a 2nd AP can occur provided the 2nd stimulus is big enough
when does absolute Refractory period occur?
during depolarisation and repolarisation
when does relative Refractory period occur?
hyperpolarisation
When do Na channels close and do they take long to come out of inactivation?
they close after AP is produced
Na channels slowly come out of inactivation
what is all or nothing principle in APs?
Once the threshold is reached a response of the same magnitude occurs despite magnitude of stimulus
2 types of cardiac APs?
myocyte (non-pacemaker)
Pacemaker
Why do pacemaker cells have no true Resting potential?
because they are undergoing continuous, spontaneous depolarisation
Describe the AP of myocyte (non-pacemaker) cells?
Phase 4 (RP): K channels open, K ions leave cell - membrane is more negative (-90mV)
some Ca leaks in, taking MP to -70mV - threshold reached
Phase 0 (depolarisation): once threshold is reached, Na channels open, rapid Na influx to allow rapid depolarisation
Phase 1 (initial repolarisation): Na channels close, K channels open, outward K efflux (MP drops)
Phase 2 (plateau): Ca channels open, allows Ca entry, this counterbalances the K efflux, resulting in a plateau
Phase 3 (repolarisation): K continues to leave, Ca channels close, K efflux allows return of RP
What key feature of Phase 2 plateau during the mycocyte AP is important?
The ca channels opening and allow ca entry allow myosin contraction of the heart
Describe the AP of pacemaker cells?
phase 4: Na moves into cells, slowly depolarises until threshold met 0 UNSTABLE RP
phase 0 (depolarisation): strong Ca influx, allows for rapid depolarisation
phase 3 (repolarisation): K moves out of cell, cell repolarises
NO PHASE 1 AND 2 - NO PLATEAU
Why dont Na channel blockers work on pacemaker cells?
this is because Ca is required for depolarisation of pacemaker cells not Na
Moa of NCBs and indication?
- target phase 0 of myocytes (depolarisation)
- slower depolarisation
- slower AP transmission through heart cells
- reduced conduction velocity (NEGATIVE DROMOTROPY)
what is a dromotropic agent?
positive: agent which increases rate of conduction through AV node
negative: decrease in conduction velocity of AP through heart
What effect do open Na channels have on permeability?
When Na channels closed = no permeability
when Na channels open = inc permeability
What is the consequence of inc Na permeability on membrane potential?
The membrane potential becomes more positive as eqm potential for Na is 60mV
What does eqm potential mean?
The membrane potential at which there is no net movement of an ion across the plasma membrane into or out of the cell
How is -ve Resting membrane potential (RMP) maintained inside the cell?
the negative RMP is created and maintained by increasing the concentration of cations outside the cell (in the extracellular fluid) relative to inside the cell (in the cytoplasm)
The negative charge within the cell is created by the cell membrane being more permeable to K+ movement than Na+ movement.
Na/K pumps move 2 K ions inside the cell as 3 Na ions are pumped out to maintain the negatively charged membrane inside the cell
this helps maintain the resting potential.
How is the negative charge maintained inside the cell?
The negative charge within the cell is created by the cell membrane being more permeable to K+ movement than Na+ movement.
high conc of K+ within the cell,
high Na+ conc outside the cell
cell membrane has more K channels than Na channels
Therefore, K diffuses out of the cell at a much faster rate than Na leaks in.
More cations leaving the cell than entering it causes the interior of the cell to be negatively charged relative to the outside of the cell.
difference between myocyte and pacemaker depol?
pacemaker cells: need ca for depol
myocyte: need Na for depol
Most local anaesthetic drugs are described as ‘use dependent ion channel inhibitors”. What is meant by this?
A use-dependent inhibitor binds an ion channel when it is inactive and only functions when the channel is activated
In doing so, these drugs increase the refractory period
and inhibit high-frequency action potentials
while not affecting normal frequency action potentials
