‘Eventless’ InsP₃‐dependent SR‐Ca²⁺ release affecting atrial Ca²⁺ sparks

Abstract

Key points• Inositol 1,4,5-trisphosphate receptors (InsP 3 Rs) are functionally expressed in cardiac myocytes.• The influence of inositol 1,4,5-trisphosphate-induced sarcoplasmic reticulum (SR)-Ca 2+ release (IP3ICR) on atrial excitation-contraction coupling (ECC) under physiological and pathophysiological conditions remains elusive.• The present study focuses on local IP3ICR and its functional consequences for ryanodine receptor (RyR) activity and subsequent Ca 2+ -induced Ca 2+ release in atrial myocytes.• Here we show significant SR-Ca 2+ flux, but eventless SR-Ca 2+ release through InsP 3 Rs.• We suggest a new mechanism based on eventless and highly efficient InsP 3 -dependent SR-Ca 2+ flux as a crucial mechanism of functional cross-talk between InsP 3 Rs and RyRs, which may be an important factor in the modulation of ECC sensitivity.Abstract Augmented inositol 1,4,5-trisphosphate receptor (InsP 3 R) function has been linked to a variety of cardiac pathologies, including cardiac arrhythmia. The contribution of inositol 1,4,5-trisphosphate-induced Ca 2+ release (IP3ICR) in excitation-contraction coupling (ECC) under physiological conditions, as well as under cellular remodelling, remains controversial. Here we test the hypothesis that local IP3ICR directly affects ryanodine receptor (RyR) function and subsequent Ca 2+ -induced Ca 2+ release in atrial myocytes. IP3ICR was evoked by UV-flash photolysis of caged InsP 3 under whole-cell configuration of the voltage-clamp technique in atrial myocytes isolated from C57/BL6 mice. Photolytic release of InsP 3 was accompanied by a significant increase in the Ca 2+ release event frequency (4.14 ± 0.72 vs. 6.20 ± 0.76 events (100 μm) −1 s −1 ). These individual photolytically triggered Ca 2+ release events were identified as Ca 2+ sparks, which originated from RyR openings. This was verified by Ca 2+ spark analysis and pharmacological separation between RyR and InsP 3 R-dependent sarcoplasmic reticulum (SR)-Ca 2+ release (2-aminoethoxydiphenyl borate, xestospongin C, tetracaine). Significant SR-Ca 2+ flux but eventless SR-Ca 2+ release through InsP 3 R were characterized using SR-Ca 2+ leak/SR-Ca 2+ load measurements. These results strongly support the idea that IP3ICR can effectively modulate RyR openings and Ca 2+ spark probability. We conclude that eventless and highly efficient InsP 3 -dependent SR-Ca 2+ flux is the main mechanism of functional cross-talk between InsP 3 Rs and RyRs, which may be an important factor in the modulation of ECC sensitivity.

Intracellular calcium channels in protozoa

“…It also occurs in the ER of rat sensory neurons (Solovyova and Verkhratsky, 2003) and in mammalian skeletal muscle RyRs and IP 3 Rs cooperate to activate Ca 2+ -signaling via the SR (Tjondrokoesoemo et al , 2013). A similar cooperativity has been detected in atrial cells of the heart (Horn et al , 2013). …”

“…Pt CRC-II/IP 3 Rs are restricted to the contractile vacuole complex (serving in fresh water organisms for the expulsion of water and of some ions, including an excess of Ca 2+ ) and, therefore, may fine-tune Ca 2+ homeostasis by partial reflux of Ca 2+ (Ladenburger et al , 2006). Spontaneous Ca 2+ puffs are seen along the tubular extensions of this organelle, indicating constitutively active IP 3 R type channels - a phenomenon reported later on also for a chicken lymphocyte cell line (Cardenas et al , 2010) and mammalian atrial myocytes (Horn et al , 2013). Pt CRC-III molecules are associated with recycling vesicles engaged in phagosome formation (Ladenburger and Plattner, 2011).…”

IP3R activity increases frequency of RyR-mediated sparks by elevating dyadic Ca2+

“…Crosstalk between IP 3 Rs and RyRs, in which activation of IP 3 Rs via elevated IP 3 leads to recruitment of neighbouring RyRs receptors, leading to larger Ca 2+ release, was first suggested in smooth muscle cells [10]. Similar interaction between IP 3 Rs and RyRs has also been proposed in embryonic myocytes [11,12], atrial cardiac myocytes [13][14][15], spontaneously hypertensive rat (SHR) myocytes [8], and rabbit ventricular myocytes [16]. Given the lower abundance and Ca 2+ flux of IP 3 Rs relative to RyRs, how they can affect ECC remains poorly understood.…”

“…To test the role that IP 3 Rs play in spark activation, we next considered which dyad trigger settings were sufficient to generate a spark. Experiments on cardiac and smooth muscle cells suggested that IP 3 Rs may not create a spark by themselves, but can facilitate neighbouring RyR opening [10,12,13]. Therefore we tested how one dyad will behave when: (a) no initiation is applied; (b) 5 IP 3 Rs are opened at t = 0 ms; (c) 5 Simulation results shown in Fig.…”

IP3 and Ca2+ signals in the heart: boost them or bust them?

“…In cardiomyocytes, particularly in atrial cells where IP 3 Rs are more abundant, a modulatory function of IP 3 Rs on CICR has been recognized (Mackenzie et al 2002). IP 3 Rs may indeed participate in Ca 2+ signalling, secondary to acute or chronic stimulation of membrane receptors linked to the phospholipase C (PLC)-IP 3 signalling pathways, such as endothelin (ET) or angiotensin (AT) II receptors (Horn et al 2013). Recently, it has been found that IP 3 Rs located in the nuclear envelope are involved in excitation-transcription coupling, thereby participating in the control of gene expression programmes.…”