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Mitochondria Regulate the Ca2+–Exocytosis Relationship of Bovine Adrenal Chromaffin Cells

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Mitochondria Regulate the Ca2+–Exocytosis Relationship of Bovine Adrenal Chromaffin Cells The Journal of Neuroscience, November 1, 1999, 19(21):9261–9270 Mitochondria Regulate the Ca21–Exocytosis Relationship of Bovine Adrenal Chromaffin Cells David R. Giovannucci,1 Michael D. Hlubek,2 and Edward L. Stuenkel1 Departments of 1Physiology and 2Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622 The present study expands the contemporary view of mito- entered via voltage-activated Ca 21 channels. Disruption of chondria as important participants in cellular Ca 21 dynamics cellular Ca 21 homeostasis by poisoning mitochondria en- and provides evidence that mitochondria regulate the supply of hanced the secretory responsiveness of chromaffin cells by release-competent secretory granules. Using pharmacological increasing the amplitude of the transient rise and the time 21 D 21 probes to inhibit mitochondrial Ca import, the ability of mi- course of recovery to baseline of the evoked [Ca ]c. The tochondria to modulate secretory activity in single, patch- enhancement of the secretory response was represented by clamped bovine chromaffin cells was examined by simulta- significant deviation of the Ca 21–exocytosis relationship from a 21 D neously monitoring rapid changes in membrane surface area standard relationship that equates Ca influx and Cm. Thus, D 21 21 ( Cm ) and cytosolic Ca levels ([Ca ]c ). Repetitive step mitochondria would play a critical role in the control of secre- depolarizations or action potential waveforms were found to tory activity in chromaffin cells that undergo tonic or repetitive 21 m 21 raise the [Ca ]c of chromaffin cells into the 1 M to tens of depolarizing activity, likely by limiting the Ca -dependent ac- micromolar range. Inhibiting mitochondria by treatment with tivation of specific proteins that recruit or prime secretory gran- carbonyl cyanide p-(trifuoro-methoxy)phenylhydrazone, anti- ules for exocytosis. mycin–oligomycin, or ruthenium red revealed that mitochondria Key words: membrane capacitance; exocytosis; FCCP; are a prominent component for the clearance of Ca 21 that fura-2; furaptra; readily releasable pool 1 The immediate exocytotic release of neurotransmitters from syn- function as a cytosolic Ca 2 buffer of low affinity and high aptic vesicles at the active zone of a synaptic bouton is governed capacity (Lehninger et al., 1967; Blaustein et al., 1977; Blaustein 1 by Ca 2 influx and the rapid collapse of microdomains of high et al., 1978; Carafoli and Crompton, 1978; Carafoli, 1979; Ni- 21 [Ca ]c by diffusion (Neher, 1998). Colocalization of secretory cholls and Akerman, 1982; Gunter et al., 1994). Pharmacologi- 1 granules and Ca 2 entry sites has also been proposed for adult cally induced or pathophysiologically mediated mitochondrial 1 bovine and calf chromaffin cells (Robinson et al., 1995; Elham- dysfunction leads to altered Ca 2 homeostasis in neurons dani et al., 1998). In contrast, the exocytotic release of cat- (Thayer and Wang, 1995; Budd and Nicholls, 1996b; Schinder et echolamines from secretory granules is sensitive to changes in the al., 1996; Wang and Thayer, 1996; White and Reynolds, 1997; 1 exogenous Ca 2 buffering capacity. This observation may be Nicholls and Budd, 1998). In addition, the notion that mitochon- explained by indications that only a small subset of granules dria participate in shaping changes in cytosolic calcium concen- 1 2 21 colocalize with Ca channels (Horrigan and Bookman, 1994; tration ([Ca ]c) during normal cellular functioning has recently Klingauf and Neher, 1997). Although there is currently little 1 been bolstered through the simultaneous monitoring of changes direct evidence for mitochondrial Ca 2 dynamics regulating se- 21 21 21 in [Ca ]c and mitochondrial free Ca levels ([Ca ]m) (Sheu cretory responsiveness, the concept is reasonable because mito- and Jou, 1994; Hajnoczky et al., 1995; Sparagna et al., 1995; Jou chondria have been postulated to function as the predominant et al., 1996; Robb-Gaspers et al., 1998; Simpson and Russell, 21 Ca clearance mechanism during prolonged or repetitive 1998). Despite the evidence, there remains a long-standing con- 21 1 stimulus-activated Ca influx in sympathetic neurons (Thayer troversy as to the functional relevance of mitochondrial Ca 2 and Miller, 1990; Friel and Tsien, 1994; Werth and Thayer, 1994), import during neuronal activity. adrenal chromaffin cells (Herrington et al., 1996; Park et al., 1996; Modulation of the amplitude and kinetics of the evoked Babcock et al., 1997; Xu et al., 1997), gonadotropes (Hehl et al., D 21 [Ca ]c exerts a regulatory influence on multiple steps that 1996), and neuroendocrine nerve endings (Stuenkel, 1994; Gio- control the release of neurotransmitters (Herrington et al., 1996). vannucci and Stuenkel, 1997). 21 For example, modest increases in [Ca ]c augment the recruit- Mitochondria can sequester large amounts of calcium and ment and passage of granules through the secretory pathway via 1 the interaction of Ca 2 ions with distinct protein targets (Bittner Received Jan. 12, 1999; revised Aug. 17, 1999; accepted Aug. 20, 1999. and Holz, 1992; von Ruden and Neher, 1993; Neher and Zucker, This work was supported by National Institutes of Health Grant NS36227 to E.L.S. 1993; Zucker, 1996; Bennett, 1997; Neher, 1998). In addition, it is We thank Drs. James Herrington, Ronald Holz, Mary Bittner, and Brandi Soldo for valuable discussion. generally thought that the efficient secretion of neuropeptide or Correspondence should be addressed to David Giovannucci’s present address: catecholamine requires a level of stimulatory activity that is Department of Pharmacology and Physiology, School of Medicine and Dentistry, strong enough to evoke mitochondrial participation (Peng and University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642. E-mail: [email protected]. Zucker, 1993; Nowycky et al., 1998). In the current study, the Copyright © 1999 Society for Neuroscience 0270-6474/99/199261-10$05.00/0 hypothesis that mitochondria regulate secretory activity by lim- 9262 J. Neurosci., November 1, 1999, 19(21):9261–9270 Giovannucci et al. • Mitochondria and Secretion 21 iting rises in [Ca ]c and the subsequent activation of specific Sony, Tokyo, Japan) and stored for playback on a video cassette recorder (Betamax SL-2700; Sony). proteins that recruit or prime secretory granules for exocytosis 21 1 1 Epifluorescence measurement of [Ca ] . To determine D[Ca 2 ] , 150 was tested by monitoring stimulus-evoked changes in [Ca 2 ] and c c c mM fura-2 or furaptra was included in the intracellular recording solu- the secretory activity of single bovine chromaffin cells after tion, and the fluorescence was monitored using dual wavelength mi- 1 selective pharmacological inhibition of mitochondrial Ca 2 crospectrofluorometry (SPEX Industries, Edison, NJ). Individual chro- transport. maffin cells were optically isolated using a 10 mm pinhole stop and then illuminated by epifluorescence through a 403 oil immersion objective MATERIALS AND METHODS (NA of 1.30) with alternating excitation wavelengths of 340 and 380 nm. The emission at 510 nm was measured by photomultiplier (15–100 Preparation of bovine chromaffin cells. Primary dissociated cells from the 21 msec/point), and the [Ca ]c was obtained using the ratiometric method medullas of fresh bovine adrenal glands obtained from a local commer- (Grynkiewicz et al., 1985): cial slaughterhouse (Murco, Plainwell, MI) were prepared by a collage- 1 nase digestion procedure (Bittner et al., 1986). Cultures were maintained @Ca2 # 5 K *b@~R 2 R !/~R 2 R!#. in DMEM–F-12 (BioWhittaker, Walkersville, MD) containing 10% heat C D min max inactivated FCS. Cells were cultured as monolayers on collagen-coated Fura-2 and furaptra signals were calibrated using a solution similar to the m glass coverslips (32 g/ml in 0.01 N HCl), which formed the bottoms of intracellular patch recording solution and containing either nominal (10 21 21 35 mm culture dishes (500,000–1,000,000 cells per dish). Before the start mM EGTA, no added Ca ) or saturating (2.9 mM) free [Ca ] and 21 of an experiment, culture medium was replaced by superfusion with constant free [Mg ] of 0.74 mM (determined using Patcher’s Power ; physiological saline for 20 min. Experiments were performed 1–8 d Tools XOP; Dr. Francisco Mendez, Department of Membrane Biophys- after the preparation of the cell cultures. ics, Max-Planck-Institute for Biophysical Chemistry, Gottingen, Germa- Electrophysiological recording of Ica and Cm. Standard whole-cell and ny). After subtraction of background autofluorescence measured before perforated patch-clamp methods were used to evoke and record calcium b rupture of the cell membrane patch, Rmin, Rmax, and were determined currents and measure small, time-resolvable changes in membrane ca- to be 0.35, 11.4, and 9.6 for fura-2, and 0.47, 6, and 8.3 for furaptra, pacitance (DC ) from single chromaffin cells using a modified Axopatch m respectively. A KD value for fura-2 of 224 nM was taken from the 200A amplifier (Axon Instruments, Foster City, CA) and phase-tracking literature (Grynkiewicz et al., 1985), and b was determined by multiply- software (Pulse Control; Drs. Jack Herrington and Richard Bookman, ing K by the ratio F /F . In experiments in which the perforated D D 0 s University of Miami Medical School, Miami, FL). The Cm was moni- patch-clamp configuration was used, cells were loaded by perifusion with tored by applying a sine wave (60 mVp-p at 1201 Hz) to a holding a physiological saline solution containing 1 mM fura-2 AM or furaptra 2 potential of 90 mV. Sixteen samples per sinusoidal period were used to AM. In these cells, background autofluorescence was determined after compute one Cm point each 6.6 msec, and calibration pulses (100 fF and attainment of whole-cell configuration and washout of the dye. The 500 kV) were generated at the beginning of each trace. A train of 8 or 12 dissociation constant (KD) of furaptra has been estimated to range 50–100 msec step depolarizations from 290 to 10 mV at 0.2 or 0.5 sec m 1 between 20 and 53 M (Raju et al., 1989; Hurley et al., 1992; Naraghi, intervals was applied to evoke I , D[Ca 2 ] , and DC .
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