Flashcards in EC coupling 1 and 2 Deck (34):
What does calcium binding to troponin allow for in cardiac muscle?
• Enables the force producing interaction between the thin filaments (actin) and the myosin heads (thick filaments)
Where does the release of calcium originate in cardiac muscle contraction?
• Junctions bewteen the terminal cisternae of the SR and the plasma membrane T-tubules
Which is a bigger deal, SERCA2 or NCX?
• SERCA2 has the dominatory effect as it is in the SR and the SR surrounds each myofibril
• Also, there is less of an energy difference to get over since the SR membrane potential is about 0mV
What is the sequence of event leading to cardiac myocyte contraction?
• Calcium enters via DHPR (L-type calcium channel)
• Activates RyR2 to cause larger flux of Calcium from SR into mycoplasm
• Calcium activates contraction by binding to troponin on thin filaments
• Calcium is removed from the mycoplasm by SERCA2 and NCX
Where are the dihydropyridine receptors located in cardiac myocytes?
• On the cytoplasmic side of the T-tubule membrane
Where is the NCX pump in the myocyte?
• It is on the myocyte plasma membrane, within the T-tubule
• Thus, it is pumping ions IN the cytoplasm or OUT OF the cytoplasm (not the SR)
• Thus it is an important source of calcium influx and efflux in the myocyte
What is the exchange rate in the NCX pump?
• 3 Na for one Calcium
• Can go either way
• The direction it runs depends on both membrane potential and the gradients for sodium and calcium
• Switching potential
○ V = 3Ena - 2Eca
If [Na]o = 150mM, [Na]I = 15mM, [Ca]o = 2mM, [Ca]I = 100nm, what will the switching potential be of the NCX pump?
• Vr = 3Ena - 2Eca
• Vr = 3(58mV) - 2(124mV)
• Vr = -74mV
What does a Vr of -74mV actually mean?
• Calcium will be extruded untill [Ca]inside falls to 100nm
• At which point net movement via NCX would be zero
• However, if [Na]inside were to increase, there would be a decrease in Ena and a corresponding left shift of Vr
• This would result in an increase in the steady-state level of [Ca]inside
What role does the I-ncx play in the nodal cells and their automaticity?
• There is SR calcium release independent of plasma membrane dynamics
• Calcium release into the myoplasm will result in net inward current through the I-ncx (if that doesn't make sense go back to notes, think how many na for ca)
• Net inward current will depolarize the cell, an important part of nodal cell behavior
Why is it that at phase 0 (upstroke) of the fast cardiac action potential, I-ncx is outward, while it is inward during phase 3 (repolarization)?
• I-ncx, during depolarization, is a significant source of calcium entry.
○ The current out is because of sodium (3na for every ca)
• It also helps extrude Calcium during repolarization so that contraction isn't favored anymore
○ Current "in" because 3na for every ca
Beta blockers, angiotensin antagonists, and diuretics all share the same underyling goal as cardiac glycosides (drugs not used so much anymore). What is that goal?
• Cardiac glycosides were used in cardiac failure (insufficient contractility)
• They blocked Na/K pump which led to overall increase in intracellular sodium
• Intracellular sodium increase led to increase in SR stored Ca and intracellular Ca (through the Vr and the NCX)
• Led to greater contractility
What is meant by CDI and what channel is it super important for?
• CDI = calcium dependent inactivation
• Super important for L-type Calcium channels on the myosplasmic membrane in the T-tubules
• These are in direct relationship with RyR2 receptors, so there is interplay between them
What might happen to the L-type calcium channels and RyR2 receptors if SR calcium level was too LOW?
• Too little efflux from RyR2 would mean that there is not the proper amount/time frame of CDI on the L-type calcium channel
• Will mess with the time the L-type channels are open, messing with membrane depolarization
What might happen to the L-type calcium channels and RyR2 receptors if SR calcium level was too HIGH?
• Too much efflux from RyR2 would increase local [ca] around the cytoplasmic portio of the L-type calcium channel
• This would lead to faster CDI and mess with the depolarization of the cell
What does CDI do to SR calcium levels?
• Helps keep it constant
• Less CDI if less SR levels, so allows more Ca influx from outside to be later pumped into SR
• More CDI if higher SR levels, leading to less calcium from outside and reduction of SR stores back to normal
What are the 4 things that circulating epinephrine and norepinephrine from sympathetic nerve terminals do?
• Increase heart rate (positive chronotropy)
○ Raising firing rate of pacemaker cells in SA node
• Alter propagation through conduction pathways
• Increase contractile force (positive inotropy)
• Increase rate of relaxation (positive lusitropy)
What does phosphorylation of the L-type Ca channel by PKA do?
• DHPR with Cav1.2 is the example
• Increases amplitude of L-type Ca current
• Increases trigger of RyR2 activation
• Leads to increase in SR stores
What are PKA targets in the cardiac myocyte that help to increase inotropy and lusitropy?
• L-type Calcium channel
• RyR2 channels
• Phospholamban (PLB)
How do epinephrine and norepinephrine accomplish increasing both inotropy and lusitropy?
• Through Beta-adrenergic receptors
• GPCRs that are Gs in nature
• Elevate cAMP levels, and lead to PKA activation
• PKA targets:
○ L-type Calcium channel
○ RyR2 channels
○ Phospholamban (PLB)
What does PKA phosphorylation of the RyR2 receptor accomplish?
• Increased sensitivity to calcium, so it's easier to trigger and release SR stores
PKA phosphorylation of what protein will lead only to positive lusitropy?
• Troponin. Allows for quicker muscle relaxation
PKA phosphorylation of what proteins will lead to postive inotropy AND positive lusitropy?
• PLB, which is the inhibitor of SERCA2
PKA phosphorylation of what proteins will lead to positive inotropy?
• L-type Calcium channels (DHPR)
• RyR2 receptors
What does phosphorylation of troponin by PKA do?
• Speeds the rate of calcium dissociation from thin filaments
• Contributes to faster relaxation and positive lusitropy
What does PKA phosphorylation of PLB do?
• PLB is an inhibitor of SERCA2, which inhibits Calcium pumping activity
• PLB phosphorylation by PKA will inhibit the inhibitor, allowing for increase in SR calcium stores because more Ca being pumped in
• Speeds relaxation and increases the SR stores
What's up with Timothy syndrome?
• Results in syncope, cardiac arrhythmias and sudden death
• Congenital heart disease
• Intermittent hypoglycemia, immune deficiency and cognitive abnormalities (autism) also seen
• Linked to mutations in L-type calcium channels
The mutations in timothy syndrome of the L-type calcium channels have what overall effect on the heart?
• AV block
• Prolonged Q-T intervals
○ Indicative of prolonged ventricular action potential
• Episodes of polymorphic ventricular tachycardia
TS and TS2 patients have what and display what?
• They have point mutations in their L-type calcium channels
• These are expressed in several tissues, including the heart
• TS = G406R in exon 8
• TS2 = G402S and G406R in exon 8
• Both mess with CDI
What's up with Brugada syndrome?
• Aka = sudden unexplained death syndrome
• Associated with many ECG alterations
• Linked to cardiac sodium channel Nav1.5 mutations, part of the I-k-to channel and ankyrin
• Ankyrin links sodium channel to cytoskelaton
• Some patients alos have Cav1.2 mutations in the L-type calcium channel
What do the many mutations that cause Brugada syndrome end up doing?
• Large reduction in the magnitude of L-type Calcium current
• A93V and G490R mutations may be a consequence of impaired membrane trafficking
• SHORTENED Q-T interval
What does CPVT stand for?
• Catecholaminergic polymorphic ventricular tachycardia
What is the main problem (general) in CPVT?
• Calcium leak, due to the mutations in CasQ2 and RyR2 proteins, will lead to depolarizations
• Through action/function of I-ncx
• Initiates arrhythmias