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Calcium-Induced Calcium Release in Smooth Muscle7 Loose Coupling

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Calcium-Induced Calcium Release in Smooth Muscle7 Loose Coupling View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central Calcium-induced Calcium Release in Smooth Muscle✪ Loose Coupling between the Action Potential and Calcium Release M.L. Collier, G. Ji, Y.-X. Wang, and M.I. Kotlikoff From the Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6046 abstract Calcium-induced calcium release (CICR) has been observed in cardiac myocytes as elementary cal- cium release events (calcium sparks) associated with the opening of L-type Ca2ϩ channels. In heart cells, a tight coupling between the gating of single L-type Ca2ϩ channels and ryanodine receptors (RYRs) underlies calcium re- lease. Here we demonstrate that L-type Ca2ϩ channels activate RYRs to produce CICR in smooth muscle cells in the form of Ca2ϩ sparks and propagated Ca2ϩ waves. However, unlike CICR in cardiac muscle, RYR channel open- ing is not tightly linked to the gating of L-type Ca2ϩ channels. L-type Ca2ϩ channels can open without triggering Ca2ϩ sparks and triggered Ca2ϩ sparks are often observed after channel closure. CICR is a function of the net flux of Ca2ϩ ions into the cytosol, rather than the single channel amplitude of L-type Ca2ϩ channels. Moreover, unlike CICR in striated muscle, calcium release is completely eliminated by cytosolic calcium buffering. Thus, L-type Ca2ϩ channels are loosely coupled to RYR through an increase in global [Ca2ϩ] due to an increase in the effective distance between L-type Ca2ϩ channels and RYR, resulting in an uncoupling of the obligate relationship that exists in striated muscle between the action potential and calcium release. key words: calcium-induced calcium release • smooth muscle • Ca2ϩ sparks • excitation–contraction cou- pling • action potential signaling INTRODUCTION Ca2ϩ channel, which is sensed by the RYR, resulting in RYR gating, and several lines of evidence indicate that In striated muscle excitation–contraction (E-C)1 cou- the opening of a single L-type Ca2ϩ channel triggers a pling is initiated by the gating of sarcolemmal L-type Ca2ϩ spark in an obligatory fashion (Niggli and Led- Ca2ϩ channels, which trigger the release of calcium erer, 1990; Cannell et al., 1995; Lopez-Lopez et al., from ryanodine receptors (RYRs) on the sarcoplasmic 1995; Santana et al., 1996; Lipp and Niggli, 1996; Col- reticulum (Endo, 1977; Fabiato, 1983; Nabauer et al., lier et al., 1999). This tight coupling between gating of 1989; Tanabe et al., 1990; McPherson and Campbell, the voltage-dependent sarcolemmal channel and the 1993). While the mechanism of coupling between L-type sarcoplasmic reticular release channel underlies the Ca2ϩ channels and RYRs is different in skeletal and full mobilization of Ca2ϩ that occurs in cardiac myo- cardiac myocytes, in both cell types local interactions cytes with each action potential. between these proteins underlie calcium release. In RYRs are widely expressed in nonsarcomeric (smooth) skeletal myocytes, calcium entry is not required for cal- muscle, neurons, and nonexcitable cells, although their cium release (Armstrong et al., 1972), but gating of the role in calcium release and cellular signaling is poorly L-type Ca2ϩ channel appears to be physically coupled understood. In smooth muscle, RYRs are expressed on to RYR opening (Tanabe et al., 1990; Nakai et al., the sarcoplasmic reticulum (Carrington et al., 1995; 1998). Calcium entry through L-type Ca2ϩ channels Lesh et al., 1998) and triggered Ca2ϩ release has been triggers calcium-induced calcium release (CICR) in inferred from measurements of calcium-activated mem- heart cells (Fabiato, 1985; Nabauer et al., 1989), result- brane currents and spatially averaged [Ca2ϩ] (Zholos ing in localized calcium release, termed Ca2ϩ sparks i et al., 1992; Ganitkevich and Isenberg, 1992, 1995), but (Cheng et al., 1993; Cannell et al., 1995; Lopez-Lopez little direct evidence of CICR exists and the function of et al., 1995). This coupling process involves a local in- RYRs in E-C coupling is poorly understood. Spontane- crease in [Ca2ϩ] in the microdomain of the L-type i ous Ca2ϩ sparks have been reported in smooth muscle (Nelson et al., 1995; Mironneau et al., 1996; Gordienko Address correspondence to Michael I. Kotlikoff, Department of Ani- et al., 1998), and recent experiments combining confo- mal Biology, University of Pennsylvania, 3800 Spruce Street, Philadel- cal microscopy and patch-clamp techniques have dem- phia, PA 19104-6046. Fax: 215-573-6810; E-mail: [email protected] onstrated localized calcium release during depolarizing ✪The online version of this article contains supplemental material. 1Abbreviations used in this paper: CICR, calcium-induced calcium re- voltage-clamp steps (Arnaudeau et al., 1997; Imaizumi lease; E-C, excitation–contraction; RYR, ryanodine receptor; SR, sar- et al., 1998), further supporting the existence of CICR coplasmic reticulum. in smooth muscle. Here we show that the L-type Ca2ϩ 653 J. Gen. Physiol. © The Rockefeller University Press • 0022-1295/2000/05/653/10 $5.00 Volume 115 May 2000 653–662 http://www.jgp.org/cgi/content/full/115/5/653 current (ICa) evokes CICR in single urinary bladder my- start of the voltage step. Images were analyzed using either Intervi- ocytes and establish the relationship between L-type sion software (Silicon Graphics Inc.) or a custom written analysis Ca2ϩ channel opening and RYR-mediated calcium re- program using Interactive Data Language software (Research Sys- tems Inc.), kindly provided by Drs. Mark Nelson and Adrian lease in smooth muscle. Bonev (Dept. of Pharamacology, University of Vermont, Burling- ton, VT). In all x–y images, a mean background fluorescence value MATERIALS AND METHODS was determined and subtracted from each pixel, and the images Cell Isolation were smoothed using a 3 ϫ 3 pixel median filter. Mean baseline fluorescence intensity (Fo) of a cell was obtained by averaging the Male New Zealand White rabbits were anesthetized (50 mg/kg first six to eight images that did not exhibit transient rises in intra- ketamine, 5 mg/kg xylazine IM) and killed (100 mg/kg pento- cellular Ca2ϩ. Profiles of line-scan images were obtained over a barbital i.v.) in accordance with an approved laboratory animal 1-␮m region and Fo was obtained by averaging the fluorescence of protocol. The urinary bladder was removed, dissected in ice-cold 30 pixels before a depolarizing step. Ratios of images (F/Fo) and oxygenated physiological salt solution, minced, and suspended profiles were constructed to reflect changes in fluorescence inten- in modified collagenase type II (Worthington Biochemical), 1 sity over time. The previously described pseudo-ratio equation 2ϩ mg/ml protease type XIV and 5 mg/ml bovine serum albumin (Cheng et al., 1993) was used to estimate [Ca ]i, using a Kd value 2ϩ (Sigma-Aldrich) at 37ЊC for 35–40 min. Digested tissue was tritu- for fluo-4 of 345 nM and assuming basal [Ca ]i to be 100 nM. The rated with a wide-bore Pasteur pipette and passed through a 125- Ca2ϩ spark criteria were a localized increase in fluorescence (F/ ␮m nylon mesh; cells were concentrated by low speed centrifuga- Fo) Ն 1.5, occurring in 20–30 ms, with a decay time of 50–80 ms. tion, washed with fresh medium, resuspended, and stored at 4ЊC. Ca2ϩ spark latencies were calculated as the time from the start of the voltage pulse to the point at which the fluorescence exceeded 2ϩ Electrophysiology 5% of Fo, and were calculated for Ca sparks occurring within the first voltage-clamp step of an experiment, so as not to bias results Single myocytes were placed in a chamber mounted on an in- 2ϩ by an increase in [Ca ]i resulting from preceding voltage-clamp verted Nikon TE300 microscope (Nikon) and whole-cell record- steps. Ca2ϩ spark probability was calculated in the following man- ings made as previously described (Wang and Kotlikoff, 1997). In ner. Voltage-clamp steps were analyzed to determine whether or most experiments, pipettes were filled with (mM): 127 cesium not a Ca2ϩ spark occurred during a specific clamp step. Currents glutamate, 10 HEPES (cesium-salt), 19 TEACl, 0.1 Tris-GTP, 1 associated with each step were integrated to determine net Ca2ϩ Mg-ATP, 5 Tris2-creatine phosphate, and 0.1 fluo-4 (pentapotas- flux, the fluxes were binned, and the probability was calculated by sium salt) at pH 7.2. Heparin (2–5 mg/ml) was added to the in- dividing the number of experiments in which a Ca2ϩ spark was ternal solution in some experiments. In experiments where the evoked by the total number of experiments in the bin. Thus, the buffering capacity of the internal solution was increased, pipettes probability of a Ca2ϩ spark occurring in voltage-clamp steps after were filled with (mM): 110 CsCl, 5 HEPES (cesium-salt), 17 clamp steps in which no Ca2ϩ spark occurred is likely somewhat EGTA, 0.1 Tris-GTP, 1 Mg-ATP, 5 Tris2-creatine phosphate, and 3 higher due to the accumulation of Ca2ϩ from previous steps. 2ϩ fluo-4 (pentapotassium salt), with intracellular Ca concentra- These probabilities were fit to a Boltzmann equation of the form: tion adjusted to 100 nM at pH 7.2. The external solution con- tained (mM): 137 NaCl, 5 CsCl, 2 CaCl2, 1 NaH2PO4, 1.2 MgCl2, 1 P = 1 + -------------------, 10 HEPES, and 5 glucose at pH 7.4. Caffeine (10 mM) was ap- ()J – J ⁄ k e 50 plied to cells using a picospritzer (General Valve Corp.). Voltage- pulse protocols and the resulting membrane currents were ac- 2ϩ where J is the Ca flux, J50 is the flux at which there is a 50% quired and analyzed using pCLAMP software (Axon Instruments, probability of evoking a Ca2ϩ spark, and k is the slope factor of the Inc.).
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