With increasing stimulation fre quency, despite decreasing time available for uptake, increasing pre release SR Ca2 content is achieved only by increased rate of SR filling. This increased rate of SR filling translates into a faster decline in inhibition via the luminal sensor. enough Hence, the rate of inacti vation decreases as the frequency is increased from 0. 5 Hz to 8. 0 Hz owing to increasing SR Ca2 content in this range of frequencies. With increase in frequency, the rate dependent increase in the level of activated CaMKII in the dyadic space also causes an increased CaMKII mediated upregulation of the ryanodine receptor. This CaMKII mediated up regulation delays the onset of declining SR Ca2 content driven increase in the rate of RyR channel inactivation.
The RyR channel experiences a frequency dependent modulation by both the trigger current and the amount of activated CaMKII on its dyadic side. On its luminal side, it experi ences modulation by the luminal sensor controlling refractoriness, and the SR Ca2 content providing Inhibitors,Modulators,Libraries the drive for Ca2 through the channel. SR Ca2 content The frequency dependence of pre release Ca2 level in Inhibitors,Modulators,Libraries the SR is a result of several factors namely available myo for sequestration. the rate dependent behav ior of the SERCA pump. the frequency dependence of the release characteristics of Ry sensitive Ca2 channel. and the cumulative transmembrane Ca2 transport via ICa,L and NCX. The combined effect of these factors results in the biphasic relationship between free Ca2 content in the SR and the frequency of stimula tion. As the frequency is increased from 0.
5 Hz to 8. 0 Hz, the SR Ca2 content increases due to the following frequency dependent, active CaMKII mediated effects enhance ment of maximal uptake rate of the SERCA pump due to increase in PLB phosphorylation assisted by increasing levels Inhibitors,Modulators,Libraries of activated CaMKII. decrease in the half activation constant for the forward operation of the SERCA pump translating into increased Ca2 sensitivity of Inhibitors,Modulators,Libraries the pump for uptake. and increase in half activation constant for the backward operation of the SERCA pump, reducing tendency for back flow via the SERCA pump. The increase in SR Ca2 content is also facilitated by a CaMKII mediated enhancement Inhibitors,Modulators,Libraries in ICa,L as well as inhibition of Ca2 extrusion via NCX due to increasing myo. As the stimulation frequency is gradually increased further from 8.
0 Hz to 12. 0 Hz, a steep decrease in SR Ca2 content is observed. This frequency dependent decrease in pre release SR Ca2 content at very high stimulation frequen cies is a result of the following a decrease in maximal uptake rate of the SERCA pump along with a significant decrease in time available for resequestration of cytosolic Ca2. a decrease in Ca2 entry into the cell via selleck the trigger current ICa,L.