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Ca²⁺ regulation in guinea-pig colonic smooth muscle: the role of the Na⁺-Ca²⁺ exchanger and the sarcoplasmic reticulum

Karen N. Bradley, Elaine R. M. Flynn, Thomas C. Muir and John G. McCarron

To study the contribution of the Na⁺-Ca²⁺ exchanger to Ca²⁺ regulation and its interaction with the sarcoplasmic reticulum (SR), changes in cytoplasmic Ca²⁺ concentration ([Ca²⁺]_c) were measured in single, voltage clamped, smooth muscle cells. Increases in [Ca²⁺]_c were evoked by either depolarisation (-70 mV to 0 mV) or by release from the SR by caffeine (10 mM) or flash photolysis of caged InsP₃ (InsP₃). Depletion of the SR of Ca²⁺ (verified by the absence of a response to caffeine and InsP₃) by either ryanodine (50 µM), to open the ryanodine receptors (RyRs), or thapsigargin (500 nM) or cyclopiazonic acid (CPA, 10 µM), to inhibit the SR Ca²⁺ pumps, reduced neither the magnitude of the Ca²⁺ transient nor the relationship between the influx of and the rise in [Ca²⁺]_c evoked by depolarisation. This suggested that Ca²⁺-induced Ca²⁺ release (CICR) from the SR did not contribute significantly to the depolarisation-evoked rise in [Ca²⁺]_c. However, although Ca²⁺ was not released from it, the SR accumulated the ion following depolarisation since ryanodine and thapsigargin each slowed the rate of decline of the depolarisation-evoked Ca²⁺ transient. Indeed, the SR Ca²⁺ content increased following depolarisation as assessed by the increased magnitude of the [Ca²⁺]_c levels evoked each by InsP₃ and caffeine, relative to controls. The increased SR Ca²⁺ content following depolarisation returned to control values in approximately 12 min via Na⁺-Ca²⁺ exchanger activity. Thus inhibition of the Na⁺-Ca²⁺ exchanger by removal of external Na⁺ (by either lithium or choline substitution) prevented the increased SR Ca²⁺ content from returning to control levels. On the other hand, the Na⁺-Ca²⁺ exchanger did not appear to regulate bulk average Ca²⁺ directly since the rates of decline in [Ca²⁺]_c, following either depolarisation or the release of Ca²⁺ from the SR (by either InsP₃ or caffeine), were neither voltage nor Na⁺ dependent. Thus, no evidence for short term (seconds) control of [Ca²⁺]_c by the Na⁺-Ca²⁺ exchanger was found. Together, the results suggest that despite the lack of CICR, the SR removes Ca²⁺ from the cytosol after its elevation by depolarisation. This Ca²⁺ is then removed from the SR to outside the cell by the Na⁺-Ca²⁺ exchanger. However, the exchanger does not contribute significantly to the decline in bulk average [Ca²⁺]_c following transient elevations in the ion produced either by depolarisation or by release from the store.

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