Role of Ryanodine Receptor Subtypes in Initiation and Formation of Calcium Sparks in Arterial Smooth Muscle: Comparison with Striated Muscle

Calcium sparks represent local, rapid, and transient calcium release events from a cluster of ryanodine receptors (RyRs) in the sarcoplasmic reticulum. In arterial smooth muscle cells (SMCs), calcium sparks activate calcium-dependent potassium channels causing decrease in the global intracellular[Ca2+]and oppose vasoconstriction. This is in contrast to cardiac and skeletal muscle, where spatial and temporal summation of calcium sparks leads to global increases in intracellular[Ca2+]and myocyte contraction. We summarize the present data on local RyR calcium signaling in arterial SMCs in comparison to striated muscle and muscle-specific differences in coupling between L-type calcium channels and RyRs. Accordingly, arterial SMCCav1.2L-type channels regulate intracellular calcium stores content, which in turn modulates calcium efflux though RyRs. Downregulation of RyR2 up to a certain degree is compensated by increased SR calcium content to normalize calcium sparks. This indirect coupling betweenCav1.2and RyR in arterial SMCs is opposite to striated muscle, where triggering of calcium sparks is controlled by rapid and direct cross-talk betweenCav1.1/Cav1.2L-type channels and RyRs. We discuss the role of RyR isoforms in initiation and formation of calcium sparks in SMCs and their possible molecular binding partners and regulators, which differ compared to striated muscle.

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Calcium-Induced Calcium Release in Smooth Muscle

The Journal of General Physiology ◽

10.1085/jgp.115.5.653 ◽

2000 ◽

Vol 115 (5) ◽

pp. 653-662 ◽

Cited By ~ 111

Author(s):

M.L. Collier ◽

G. Ji ◽

Y.-X. Wang ◽

M.I. Kotlikoff

Keyword(s):

Smooth Muscle ◽

Calcium Release ◽

Striated Muscle ◽

Single Channel ◽

Ryanodine Receptors ◽

Cytosolic Calcium ◽

Heart Cells ◽

Tight Coupling ◽

Calcium Induced Calcium Release ◽

Ca2 Channels

Calcium-induced calcium release (CICR) has been observed in cardiac myocytes as elementary calcium release events (calcium sparks) associated with the opening of L-type Ca2+ channels. In heart cells, a tight coupling between the gating of single L-type Ca2+ channels and ryanodine receptors (RYRs) underlies calcium release. Here we demonstrate that L-type Ca2+ channels activate RYRs to produce CICR in smooth muscle cells in the form of Ca2+ sparks and propagated Ca2+ waves. However, unlike CICR in cardiac muscle, RYR channel opening is not tightly linked to the gating of L-type Ca2+ channels. L-type Ca2+ channels can open without triggering Ca2+ sparks and triggered Ca2+ sparks are often observed after channel closure. CICR is a function of the net flux of Ca2+ ions into the cytosol, rather than the single channel amplitude of L-type Ca2+ channels. Moreover, unlike CICR in striated muscle, calcium release is completely eliminated by cytosolic calcium buffering. Thus, L-type Ca2+ channels are loosely coupled to RYR through an increase in global [Ca2+] due to an increase in the effective distance between L-type Ca2+ channels and RYR, resulting in an uncoupling of the obligate relationship that exists in striated muscle between the action potential and calcium release.

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Role of InsP3 and ryanodine receptors in the activation of capacitative Ca2+ entry by store depletion or hypoxia in canine pulmonary arterial smooth muscle cells

British Journal of Pharmacology ◽

10.1038/sj.bjp.0707357 ◽

2007 ◽

Vol 152 (1) ◽

pp. 101-111 ◽

Cited By ~ 29

Author(s):

L C Ng ◽

S M Wilson ◽

C E McAllister ◽

J R Hume

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Ryanodine Receptors ◽

Muscle Cells ◽

Arterial Smooth Muscle ◽

Store Depletion ◽

Pulmonary Arterial ◽

Arterial Smooth Muscle Cells ◽

Pulmonary Arterial Smooth Muscle

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RYR2 Proteins Contribute to the Formation of Ca2+ Sparks in Smooth Muscle

The Journal of General Physiology ◽

10.1085/jgp.200308999 ◽

2004 ◽

Vol 123 (4) ◽

pp. 377-386 ◽

Cited By ~ 53

Author(s):

Guangju Ji ◽

Morris E. Feldman ◽

Kai Su Greene ◽

Vincenzo Sorrentino ◽

Hong-Bo Xin ◽

...

Keyword(s):

Smooth Muscle ◽

Calcium Release ◽

Ryanodine Receptors ◽

Wild Type ◽

Calcium Dependent ◽

Outward Currents ◽

Associated Proteins ◽

Kinetics Of ◽

Spontaneous Transient Outward Currents

Calcium release through ryanodine receptors (RYR) activates calcium-dependent membrane conductances and plays an important role in excitation-contraction coupling in smooth muscle. The specific RYR isoforms associated with this release in smooth muscle, and the role of RYR-associated proteins such as FK506 binding proteins (FKBPs), has not been clearly established, however. FKBP12.6 proteins interact with RYR2 Ca2+ release channels and the absence of these proteins predictably alters the amplitude and kinetics of RYR2 unitary Ca2+ release events (Ca2+ sparks). To evaluate the role of specific RYR2 and FBKP12.6 proteins in Ca2+ release processes in smooth muscle, we compared spontaneous transient outward currents (STOCs), Ca2+ sparks, Ca2+-induced Ca2+ release, and Ca2+ waves in smooth muscle cells freshly isolated from wild-type, FKBP12.6−/−, and RYR3−/− mouse bladders. Consistent with a role of FKBP12.6 and RYR2 proteins in spontaneous Ca2+ sparks, we show that the frequency, amplitude, and kinetics of spontaneous, transient outward currents (STOCs) and spontaneous Ca2+ sparks are altered in FKBP12.6 deficient myocytes relative to wild-type and RYR3 null cells, which were not significantly different from each other. Ca2+ -induced Ca2+ release was similarly augmented in FKBP12.6−/−, but not in RYR3 null cells relative to wild-type. Finally, Ca2+ wave speed evoked by CICR was not different in RYR3 cells relative to control, indicating that these proteins are not necessary for normal Ca2+ wave propagation. The effect of FKBP12.6 deletion on the frequency, amplitude, and kinetics of spontaneous and evoked Ca2+ sparks in smooth muscle, and the finding of normal Ca2+ sparks and CICR in RYR3 null mice, indicate that Ca2+ release through RYR2 molecules contributes to the formation of spontaneous and evoked Ca2+ sparks, and associated STOCs, in smooth muscle.

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Role of FKBP12.6 in cADPR-induced activation of reconstituted ryanodine receptors from arterial smooth muscle

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00843.2001 ◽

2002 ◽

Vol 282 (4) ◽

pp. H1304-H1310 ◽

Cited By ~ 64

Author(s):

Wang-Xian Tang ◽

Ya-Fei Chen ◽

Ai-Ping Zou ◽

William B. Campbell ◽

Pin-Lan Li

Keyword(s):

Smooth Muscle ◽

Gradient Centrifugation ◽

Ryanodine Receptors ◽

Critical Role ◽

Accessory Protein ◽

Open Probability ◽

Arterial Smooth Muscle ◽

Fk 506 ◽

Intracellular Ca

cADP ribose (cADPR) serves as second messenger to activate the ryanodine receptors (RyRs) of the sarcoplasmic reticulum (SR) and mobilize intracellular Ca2+in vascular smooth muscle cells. However, the mechanisms mediating the effect of cADPR remain unknown. The present study was designed to determine whether FK-506 binding protein 12.6 (FKBP12.6), an accessory protein of the RyRs, plays a role in cADPR-induced activation of the RyRs. A 12.6-kDa protein was detected in bovine coronary arterial smooth muscle (BCASM) and cultured CASM cells by being immunoblotted with an antibody against FKBP12, which also reacted with FKBP12.6. With the use of planar lipid bilayer clamping techniques, FK-506 (0.01–10 μM) significantly increased the open probability ( NP O) of reconstituted RyR/Ca2+release channels from the SR of CASM. This FK-506-induced activation of RyR/Ca2+ release channels was abolished by pretreatment with anti-FKBP12 antibody. The RyRs activator cADPR (0.1–10 μM) markedly increased the activity of RyR/Ca2+ release channels. In the presence of FK-506, cADPR did not further increase the NP O of RyR/Ca2+ release channels. Addition of anti-FKBP12 antibody also completely blocked cADPR-induced activation of these channels, and removal of FKBP12.6 by preincubation with FK-506 and subsequent gradient centrifugation abolished cADPR-induced increase in the NP O of RyR/Ca2+ release channels. We conclude that FKBP12.6 plays a critical role in mediating cADPR-induced activation of RyR/Ca2+ release channels from the SR of BCASM.

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