Late sodium current Flashcards
How is INaL produced?
INaL is produced by special gating modes of the cardiac-specific Na+ channel isoform. Heart failure (HF) slows channel gating → increases INaL,
► HF-specific Na+ channel isoform underlying these changes NOTfound.
what are the effects of increased INaL in the failing myocardium (generally, two things)
Increased INaL and the corresponding Na+ flux in failing myocardium contribute to abnormal repolarization and Increased cell Ca2+ load.
How does INaL compare to INaT in terms of activation and inactivation? what about their conductance and reversal potential?
Most human cardiac Na+ channels open transiently upon membrane depolarization and then are quickly inactivated.
However, some channels remain active, carrying INaL.
In multi-channel cell-attached patches from heterologously expressed Nav1.5 and human VCs, this late activity is arranged in two major gating modes: late scattered mode (LSM) and ‘‘burst’’ mode. The channel openings of the two gating modes have almost identical single channel conductance and the reversal potential.
what are the differences between LSM and burst modes?
LSM openings render one open voltage-independent state
but
burst mode openings exhibit one open (voltage-dependent) and two closed states (one voltage-dependent and another voltage-independent).
. Na+ channel structure has multiple links to modulatory proteins. list them
Na+ channels represent a multi-protein complex comprising not only the main pore-forming a subunit and its auxiliary b subunits, but also components of cytoskeleton, Ca2+-sensitive protein calmodulin, regulatory kinases and phosphatases, trafficking proteins, and extracellular matrix proteins embedded into lipid bilayer plasma membrane.
Modulation of INaL by lysophosphatidylcholine (LPC)
LPC is the endogenous amphiphilic lipid metabolite that accumulates in ischemic myocardium and represents a major factor causing the electrophysiological alterations that contribute to arrhythmogenesis. ►A significant prolongation of QTc interval has been recently found during early transmural ischemia in patients undergoing balloon angioplasty. ►Experimentally, LPC causes depolarization, reduction of the maximal upstroke velocity of AP, sustained abnormal rhythmic activity in Purkinje fibers, and delayed afterpotentials (DADs) in isolated tissue.
The mechanisms of the LPC effects include modifications of Na+ current
Such modifications account for a reduction of INaT and an emergence of late openings that produce a sustained Na+ current. The late openings caused by LPC form clusters of the synchronized multiple channel openings. One of the mechanisms underlying these LPC-induced modifications might be an integration of LPC into the lipid membrane, which would increase the membrane fluidity. This, in turn, enhances motility and interaction of proteins within the membrane. On the other hand, LPC can activate neuromodulation signaling via PKA and PKC, affecting Na+ channel slow inactivation
The role of INaL in AP prolongation and EADs
The relative contribution of INaL to the AP plateau in failing VCs is amplified by the reduced K+ currents in HF
►Since HF simultaneously increases and slows INaL, INaL will contribute directly to AP prolongation in HF, thus explaining APD normalization with INaL inhibition described above.
►Prolonged APD allows more time for ICaL reactivation and thus facilitates EADs.
►Since INaL contributes to AP prolongation, it thus indirectly contributes to EADs
►Accordingly, inhibiting INaL eliminates EADs likely due to APD shortening.
how does inhibition of INaL affect the APD and EADs?
Shortens the AP, eliminates EADs
what is systolic dysfunction in HF associated with and what limits it?
associated with smaller Ca2+ transient and sarcoplasmic reticulum (SR) Ca2+ content. ►The extent of deterioration of systolic function is limited by multiple compensatory mechanisms (listed below), which are indirectly linked to INaL and elevated Na+.
how does INaL affect systolic function?>
INaL and elevated [Na+]i increase Ca2+ entry via NCX and limit depression of systolic function
what are the mechanisms that limit systolic dysfunction in HF?
1) NCX function depends on [Na+] and [Ca2+] and membrane voltage. In HF VCs, increased Na+ influx (including that via INaL) shifts the NCX operation from the predominant forward mode to the reverse mode, i.e. from Ca2+ efflux to Ca2+ entry. Increased Na+ in HF thus limits SR unloading and provides additional Ca2+ influx during the AP.
In addition to preserving SR Ca2+ load, this operational shift in failing myocardium results in the direct activation of contraction during the terminal phases of the AP via the reverse mode NCX Ca2+ influx.
(2) The vast majority of studies demonstrated that NCX is upregulated in HF, therefore the above effect could be amplified by the enhanced NCX function.
(3) INaL contributes to APD prolongation and thus indirectly prolongs Ca2+ influxes via ICaL and the reverse mode NCX.
(4) INaL in HF is positively modulated by intracellular Ca2+ which could yield a new possible amplification mechanism of the Ca2+ entry. This creates a positive feedback loop from INaL via NCX to larger cell Ca2+ load, then from the larger Ca2+ load back to INaL. ►A partial blockade of the NCX also improves EC coupling in HF and reduces both EADs and DADs, indicating that NCX could be a promising therapeutic target in HF.
Why do DADs occur? are INaL currents implicated?
DADs occur due to spontaneous Ca2+ releases during diastole via the activation of the forward mode of NCX. INaL does not occur at low diastolic potentials, so it cannot have a direct contribution to DADs. However, in HF VCs INaL increases Ca2+ influx leading to SR Ca2+ overload, which, in turn, is critical for initiation of spontaneous Ca2+ release (such as Ca2+ waves) during diastole. INaL involvement in DADs is thus limited to the contribution of the INaL to the Ca2+ overload. ►On the other hand, high diastolic [Na+]i in HF decreases the forward mode NCX current and hence can attenuate the amplitude of DADs. ►This positive factor of INaL can be counterbalanced by downregulation of IK1 in HF, facilitating membrane excitations.
Role of INaL in dispersion of repolarization
The mechanisms of dispersion of repolarization in HF remain unclear. A possible mechanism involves beat-to- beat alternations and/or fluctuations in intracellular Ca2+ cycling transduced to abnormal repolarization by electrogenic feedback mechanisms. Fluctuations of Ca2+ transient can be observed in failing VCs of a canine chronic HF model. Listed are three possible indirect contributions of INaL to the beat-to-beat variability problem: (1) The INaL contribution to the abnormal Ca2+ cycling. (2) The INaL dependence on Ca2+/CaM/CaMKII. Thus INaL can serve as one of the electrogenic Ca2+ feedback mechanisms along with other Ca2+ -dependent ion currents, such as ICaL inactivation, IKs, Ito, Ca2+-activated Cl_ current, and NCX. (3) The INaL contributes to AP shape that, in turn, might cause fluctuations of Ca2+ transients.
The synchronicity of Ca2+ release depends on what?
The synchronicity of Ca2+ release depends on the state of phosphorylation of Ca2+ cycling proteins and on the AP shape the faster the repolarization, the more synchronous is the Ca2+ release. Failing VCs isolated from the infarct border zone exhibit dyssynchronous SR Ca2+ release from junctional SR.
