Luminal Ca 2+ Controls Termination and Refractory Behavior of Ca 2+ -Induced Ca 2+ Release in Cardiac Myocytes

195

367

Ca 2؉ influx through L-type Ca 2؉ channels (LTCCs) influences numerous physiological processes ranging from contraction in muscle and memory in neurons to gene expression in many cell types. However, the spatiotemporal organization of functional LTCCs has been nearly impossible to investigate because of methodological limitations. Here, we examined LTCC function with high temporal and spatial resolution using evanescent field fluorescence microscopy. Surprisingly, we found that LTCCs operated in functionally organized clusters, not necessarily as individual proteins. Furthermore, LTCC function in these clusters does not appear to be controlled by simple stochastic gating but instead by a PKCdependent switch mechanism. This work suggests that resting intracellular free calcium concentration in arterial myocytes is predominantly controlled by this process in combination with rare voltage-dependent openings of individual LTCCs. We propose that Ca 2؉ influx via persistent LTCCs may be an important mechanism regulating steady-state local and global Ca 2؉ signals.evenescent field microscopy ͉ smooth muscle ͉ sparklets

Section: Discussionmentioning

confidence: 94%

Constitutively active L-type Ca ²⁺ channels

Navedo

Amberg

Votaw

et al. 2005

195

367

“…Normally, RyR luminal Ca regulation appears to play a stabilizing role by countering the intrinsic positive feedback of Ca-induced Ca release during the release process. Specifically, dissociation of Ca from the luminal sensing sites is involved in termination of SR Ca release, permitting cardiac relaxation (9,10,27). Additionally, RyRs sensitive to [Ca] SR provide a luminal Ca-dependent leak pathway and play a role in regulating SR Ca content in cardiac muscle (11,12).…”

Section: Defective Ryr Luminal Ca Regulation As a Cause Of Abnormal Camentioning

confidence: 99%

“…During the release process, the increase in cytosolic Ca is accompanied by a simultaneous, reciprocal decline in intra-SR Ca (6)(7)(8). This reduction in [Ca] SR leads to deactivation or closure of RyRs, contributing to Cainduced Ca release termination (9,10). At the same time, stimulatory effects of high luminal Ca on RyR channel open probability are responsible for the activation of a Ca leak pathway, which plays a role in setting the SR Ca content during the diastolic phase by leaking excess Ca from the SR (11,12).…”

mentioning

confidence: 99%

Abnormal intrastore calcium signaling in chronic heart failure

Kubalova¹,

Terentyev²,

Viatchenko‐Karpinski³

et al. 2005

Self Cite

182

160

Diminished Ca release from the sarcoplasmic reticulum (SR) is an important contributor to the impaired contractility of the failing heart. Despite extensive effort, the underlying causes of abnormal SR Ca release in heart failure (HF) remain unknown. We used a combination of simultaneous imaging of cytosolic and SR intralu- excitation-contraction coupling ͉ ryanodine receptor ͉ sarcoplasmic reticulum

“…For relaxation to occur, Ca release must stop, and the released Ca must be cleared from the cytosol. Termination of CICR appears to involve changes in the functional activity of the RyR channel, which is caused by the decline of [Ca] in the SR lumen by a mechanism termed luminal Ca-dependent deactivation (3). After termination of release, most of the Ca is resequestered to the SR (2).…”

mentioning

confidence: 99%

Calsequestrin determines the functional size and stability of cardiac intracellular calcium stores: Mechanism for hereditary arrhythmia

Terentyev

Viatchenko‐Karpinski

Györke

et al. 2003

Self Cite

225

233

Calsequestrin is a high-capacity Ca-binding protein expressed inside the sarcoplasmic reticulum (SR), an intracellular Ca release and storage organelle in muscle. Mutations in the cardiac calsequestrin gene (CSQ2) have been linked to arrhythmias and sudden death. We have used Ca-imaging and patch-clamp methods in combination with adenoviral gene transfer strategies to explore the function of CSQ2 in adult rat heart cells. By increasing or decreasing CSQ2 levels, we showed that CSQ2 not only determines the Ca storage capacity of the SR but also positively controls the amount of Ca released from this organelle during excitation-contraction coupling. CSQ2 controls Ca release by prolonging the duration of Ca fluxes through the SR Ca-release sites. In addition, the dynamics of functional restitution of Ca-release sites after Ca discharge were prolonged when CSQ2 levels were elevated and accelerated in the presence of lowered CSQ2 protein levels. Furthermore, profound disturbances in rhythmic Ca transients in myocytes undergoing periodic electrical stimulation were observed when CSQ2 levels were reduced. We conclude that CSQ2 is a key determinant of the functional size and stability of SR Ca stores in cardiac muscle. CSQ2 appears to exert its effects by influencing the local luminal Ca concentration-dependent gating of the Ca-release channels and by acting as both a reservoir and a sink for Ca in SR. The abnormal restitution of Ca-release channels in the presence of reduced CSQ2 levels provides a plausible explanation for ventricular arrhythmia associated with mutations of CSQ2.