Abstract
Ca2+-induced Ca2+ release (CICR) is a well characterized activity in skeletal and cardiac muscles mediated by the ryanodine receptors. The present study demonstrates CICR in the non-excitable parotid acinar cells, which resembles the mechanism described in cardiac myocytes. Partial depletion of internal Ca2+ stores leads to a minimal activation of Ca2+ influx. Ca2+ influx through this pathway results in an explosive mobilization of Ca2+ from the majority of the stores by CICR. Thus, stimulation of parotid acinar cells in Ca2+ -free medium with 0.5 microm carbachol releases approximately 5% of the Ca2+ mobilizable by 1 mm carbachol. Addition of external Ca2+ induced the same Ca2+ release observed in maximally stimulated cells. Similar results were obtained by a short treatment with 2.5-10 microm cyclopiazonic acid, an inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase pump. The Ca2+ release induced by the addition of external Ca2+ was largely independent of IP(3)Rs because it was reduced by only approximately 30% by the inhibition of the inositol 1,4,5-trisphosphate receptors with caffeine or heparin. Measurements of Ca2+ -activated outward current and [Ca2+](i) suggested that most CICR triggered by Ca2+ influx occurred away from the plasma membrane. Measurement of the response to several concentrations of cyclopiazonic acid revealed that Ca2+ influx that regulates CICR is associated with a selective portion of the internal Ca2+ pool. The minimal activation of Ca2+ influx by partial store depletion was confirmed by the measurement of Mn2+ influx. Inhibition of Ca2+ influx with SKF96365 or 2-aminoethoxydiphenyl borate prevented activation of CICR observed on addition of external Ca2+. These findings provide evidence for activation of CICR by Ca2+ influx in non-excitable cells, demonstrate a previously unrecognized role for Ca2+ influx in triggering CICR, and indicate that CICR in non-excitable cells resembles CICR in cardiac myocytes with the exception that in cardiac cells Ca2+ influx is mediated by voltage-regulated Ca2+ channels whereas in non-excitable cells Ca2+ influx is mediated by store-operated channels.
Highlights
Influx in triggering Ca2؉-induced Ca2؉ release (CICR), and indicate that CICR in non-excitable cells resembles CICR in cardiac myocytes with the exception that in cardiac cells Ca2؉ influx is mediated by voltage-regulated Ca2؉ channels whereas in non-excitable cells Ca2؉ influx is mediated by storeoperated channels
We report that Ca2ϩ influx through SOCs is critical for Ca2ϩ release in parotid acinar cells and suggest that CICR in non-muscle cells occurs in a mechanism similar to that in cardiac myocytes, except that in cardiac myocytes Ca2ϩ influx is mediated by the L-type Ca2ϩ channel whereas in non-muscle cells Ca2ϩ influx is mediated by SOCs
Stimulation of cells infused with 10 M or higher concentrations of cADPR with 1 mM carbachol resulted with a diminished response (4 cells)
Summary
Influx in triggering CICR, and indicate that CICR in non-excitable cells resembles CICR in cardiac myocytes with the exception that in cardiac cells Ca2؉ influx is mediated by voltage-regulated Ca2؉ channels whereas in non-excitable cells Ca2؉ influx is mediated by storeoperated channels. The primary activator of RyRs in muscle cells is Ca2ϩ. RyR1 directly interacts with the voltage-regulated L-type Ca2ϩ channel. The L-type channel functions as a voltage sensor that causes membrane depolarization to undergo a conformational change and activate RyR1. Membrane depolarization results in the activation of the L-type Ca2ϩ channel and Ca2ϩ influx. The incoming Ca2ϩ serves as the trigger to activate RyR2 in the cardiac sarcoplasmic reticulum and cause the explosive Ca2ϩ release and muscle contraction [8, 10]. There is good evidence that RyRs in non-muscle cells are activated by the nucleotide cADPR [16, 17]. Activation of a Ca2ϩ signal by cADPR generally is accepted as evidence for the involvement of RyRs in generating
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