Modal gating transitions in cardiac ryanodine receptors during increases of Ca 2+ concentration produced by photolysis of caged Ca 2+

Abstract

Channel adaptation is a basic property of the sarcoplasmic reticulum Ca2+-release channels/ryanodine receptors (RyRs). It allows channel activity to decay during sustained increases in the concentration of activating Ca2+. Despite the potential physiological importance of this self-confining process, its molecular mechanism is not well understood. To define the mechanism of adaptation we studied the dynamics of cardiac Ca2+-release channel (RyR) gating using the planar lipid bilayer technique in combination with photolysis of caged Ca2+ (DM-nitrophen). Channels activated by rapid and sustained increases in Ca2+ concentration (from 0.1 to 0.5 micromol/l) displayed three distinct gating modes, manifested as current records with frequent and long openings (H-mode), with rare and short openings (L-mode), and with no openings (I-mode). H-mode channel activity occurred primarily at early times while L- and I-modes predominated at late times after the rapid Ca2+ concentration increase. The decrease in probability of H-mode, mirrored by an increase in the probability of the I-mode, proceeded with a time constant similar to that observed for spontaneous decay in channel activity (i.e., adaptation) in ensemble average records. These results indicate that RyR adaptation transpires by a shift of channel gating from a high open probability mode to low open probability and inactivated modes of the channel.

FKBP12 Activates the Cardiac Ryanodine Receptor Ca2+-Release Channel and Is Antagonised by FKBP12.6

“…Such shifts in Po (modal gating) are characteristic of RyR2 channel gating [32], [35]. Single-channel records were divided into 10 s segments and the Po of each segment was calculated.…”

Amitriptyline Activates Cardiac Ryanodine Channels and Causes Spontaneous Sarcoplasmic Reticulum Calcium Release

“…We inferred the kinetics of AMT binding by measuring the duration of the AMT induced opening bursts and the intervals between them in RyR2 channels. In the absence of AMT, RyR2 exhibited a well characterized modal gating phenomenon (Zahradníková et al, 1999) in which channels would randomly fluctuate between periods of high and low P o over periods of tens of seconds. An example of this can be seen in Fig.…”

Hysteresis in voltage-gated channels

“…Then, the RyR2 activity decays as a switch into a low open probability (LP O ) mode takes place within a few seconds 49,50 . Although the decay in RyR2 activity resembles slow inactivation, further increases in Ca 2+ concentration can further increase open probability 48,49 . Thus, the decay of the RyR2 activity was caused by a process distinct to inactivation which was dubbed “adaptation.” 49 …”