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Effects of Imperatoxin a on Local Sarcoplasmic Reticulum Ca2+ Release in Frog Skeletal Muscle

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Effects of Imperatoxin a on Local Sarcoplasmic Reticulum Ca2+ Release in Frog Skeletal Muscle View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 814 Biophysical Journal Volume 79 August 2000 814–827 Effects of Imperatoxin A on Local Sarcoplasmic Reticulum Ca2؉ Release in Frog Skeletal Muscle Alexander Shtifman,* Christopher W. Ward,* Jianli Wang,† Hector H. Valdivia,† and Martin F. Schneider* *Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, and †Department of Physiology, University of Wisconsin School of Medicine, Madison, Wisconsin 53706 USA ABSTRACT We have investigated the effects of imperatoxin A (IpTxa) on local calcium release events in permeabilized frog 2ϩ skeletal muscle fibers, using laser scanning confocal microscopy in linescan mode. IpTxa induced the appearance of Ca release events from the sarcoplasmic reticulum that are ϳ2 s and have a smaller amplitude (31 Ϯ 2%) than the “Ca2ϩ sparks” normally seen in the absence of toxin. The frequency of occurrence of long-duration imperatoxin-induced Ca2ϩ release events increased in proportion to IpTxa concentrations ranging from 10 nM to 50 nM. The mean duration of imperatoxin- induced events in muscle fibers was independent of toxin concentration and agreed closely with the channel open time in experiments on isolated frog ryanodine receptors (RyRs) reconstituted in planar lipid bilayer, where IpTxa induced opening of single Ca2ϩ release channels to prolonged subconductance states. These results suggest involvement of a single molecule 2ϩ of IpTxa in the activation of a single Ca release channel to produce a long-duration event. Assuming the ratio of full conductance to subconductance to be the same in the fibers as in bilayer, the amplitude of a spark relative to the long event indicates involvement of at most four RyR Ca2ϩ release channels in the production of short-duration Ca2ϩ sparks. INTRODUCTION According to currently accepted models, E-C coupling in Imperatoxin A (IpTxa) is a 33-amino acid peptide isolated skeletal muscle involves direct interaction between the volt- form the venom of the scorpion Pandinus imperator. This age sensor in the T-tubule, the dihydropyridine receptor peptide has three cysteine residues that stabilize its globular, ϩ (DHPR), and the Ca2 release channel of the sarcoplasmic three-dimensional (3D) structure by forming disulfide reticulum (SR), the ryanodine receptor (RyR). Activation of bridges (Zamudio et al., 1997). The primary structure of the DHPR voltage sensor causes the opening of the RyR IpTx resembles that of the Thr671-Leu690 region of the II-III ϩ ϩ a Ca2 channel and subsequent Ca2 release into the myo- loop in that both peptides display a structural motif consist- plasm, resulting in activation of the contractile apparatus ing of a cluster of basic residues followed by a hydroxylated (for a review see Meltzer et al., 1995; Schneider, 1994). amino acid (Ser or Thr) (Zamudio et al., 1997; Gurrola et Initial investigations provided evidence that the 138-amino al., 1999). Imperatoxin A interacts specifically and with ␣ acid cytoplasmic loop linking repeats II and III of the 1 high affinity with the skeletal and cardiac isoforms of RyR subunit of DHPR (II-III loop) is crucial for the E-C coupling (Tripathy et al., 1998). Direct measurements of channel in skeletal muscle (Tanabe et al., 1990). Experiments with activity with RyR reconstituted in planar lipid bilayer dem- isolated peptides from rabbit skeletal muscle have shown onstrate that addition of imperatoxin to the cytosolic side 1076 1112 specific interactions between the Arg -Asp region of induces long-duration subconductance states. The substates 671 690 the RyR1 and the Thr -Leu region of the II-III loop are ϳ30% of full conductances, regardless of the current (Leong and MacLennan, 1998). Other studies show that carrier species (Tripathy et al., 1998). IpTx increases 2ϩ a specific subsections of the II-III loop can induce Ca [3H]ryanodine binding and enhances the activity of the release from the SR (El-Hayek et al., 1995) and partially Ca2ϩ release channels; both affects are modulated in a restore skeletal-type E-C coupling in dysgenic myotubes concentration-dependent manner (Gurrola et al., 1999). To (Nakai et al., 1998). These results provide strong evidence test whether the II-III loop and IpTx interact with the same 2ϩ a that the II-III loop is the primary activator of Ca release modulatory site on RyR, competitive studies were con- in skeletal muscle; however, it is still undetermined which ducted with both peptides. The results from these experi- amino acid sequence interacts directly with the RyR. Fur- ments demonstrate that the II-III loop displaces binding of thermore, other segments of the II-III loop have been im- 2ϩ IpTxa to the Ca release channel and decreases its capacity plicated in the modulation of the RyR activity (El-Hayek et to activate RyRs (Gurrola et al., 1999), thus suggesting an al., 1995). interaction with a defined amino acid sequence of the RyR. It thus appears that IpTxa provides an important tool for elucidating the E-C coupling mechanism. Received for publication 25 February 2000 and in final form 11 May 2000. Confocal imaging has become an important approach in Address reprint requests to Dr. Martin F. Schneider, Department of Bio- monitoring Ca2ϩ release from the SR in functionally intact chemistry and Molecular Biology, University of Maryland School of Medicine, 108 N. Greene Street, Room 229, Baltimore, MD 21201. Tel.: physiological systems (Cheng et al., 1993; Tsugorka et al., 410-706-7812; Fax: 410-706-8297; E-mail: [email protected]. 1995; Klein et al., 1996; Lacampagne et al., 1996). The 2ϩ © 2000 by the Biophysical Society macroscopic [Ca ] transient appears to be a direct result of ϩ 0006-3495/00/08/814/14 $2.00 summation of individual Ca2 release events induced by 2ϩ Effects of IpTxa on Local Ca Release 815 depolarization of the fiber (Klein et al., 1997). Each discrete (x versus t) at a sampling rate of 500 Hz (2 ms/line), with the scan line and localized elevation in myoplasmic [Ca2ϩ] (Ca2ϩ spark) oriented parallel to the muscle fiber. The pixel size was 0.18 ␮minx and t ␮ x is detected as a brief elevation of fluorescence of an indi- 2msin , and the image dimensions were 138 m for and 1024 ms for t. For maximum resolution images were acquired very close to the bottom cator dye. In skeletal as well as cardiac muscle, individual surface of the fiber. Each run consisted of five images, with each succes- 2ϩ Ca sparks are believed to be released from a small cluster sive image separated from the last by a 1-s gap, acquired at the same ϩ of SR Ca2 release channels (Rios et al., 1999) or perhaps location. To avoid laser damage, the scan line was moved 0.9 ␮m perpen- even a single channel (Schneider 1999). In skeletal muscle dicular to the long axis of the fiber after each run. Ca2ϩ sparks have been shown to occur at low frequency Initial recordings were obtained while the fibers were bathed in an internal solution (control). Subsequent to this, fibers were bathed in an without activation of the voltage sensor (Klein et al., 1996). internal solution containing the appropriate concentration of IpTxa. These spontaneous Ca2ϩ release events can be activated by an increase in [Ca2ϩ] (Klein et al., 1996) or inhibited with increased [Mg2ϩ] (Lacampagne et al., 1998) in the myo- Analysis of linescan images plasm, which are both consistent with calcium-induced cal- Linescan images were first computer processed to automatically identify cium release (Klein et al., 1996). The examination of indi- and store spark locations, using a relative threshold algorithm as described 2ϩ vidual Ca release event properties provides an important by Cheng et al. (1999). This algorithm was successful at identifying the ϩ ϩ ϩ means of elucidating the mechanism underlying Ca2 re- location of short-duration Ca2 sparks; however, long-duration Ca2 re- lease during the process of E-C coupling. lease events were occasionally misidentified and were subsequently man- ually identified. After the autodetection algorithm, linescan images were In the present study we have investigated the effect of ⌬F 2ϩ converted to images of change in fluorescence ( ) by subtracting the IpTxa on localized Ca release events in permeabilized average fluorescence (F) of the five sequential images, excluding the frog skeletal muscle fibers and characterized the differences fluorescence at the identified Ca2ϩ spark locations, at each spatial location ϩ between spontaneous Ca2 sparks and imperatoxin-induced from each raw fluorescence image. Each ⌬F image was then divided by F Ca2ϩ release events. We found that IpTx induces long- to create a ⌬F/F image. a 2ϩ duration, low-amplitude Ca2ϩ release events without alter- Discrete “short-duration” Ca sparks were analyzed as previously 2ϩ described by our laboratory (Lacampagne et al., 1998). In brief, images ing the properties of Ca sparks. The frequency of the were smoothed to reduce noise (3 ϫ 3 pixel “boxcar” routine), and long-duration events is concentration dependent, in a man- identified Ca2ϩ spark locations were redisplayed in ⌬F/F. Plots of the ϩ ner suggesting the involvement of a single Ca2 release temporal (t) profiles at the spatial center of the spark were constructed by channel in the generation of an individual IpTx -induced averaging five pixels (0.9 ␮m) in x (centered at the x location of the peak a ⌬F F x long-duration Ca2ϩ release event. Some of these results value for / ). Plots of spatial ( ) distribution of fluorescence at the time of the peak were constructed by averaging three pixels (6 ms) in t (centered have been presented in abstract form (Shtifman et al., 1999).
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