Action potential refractory period in ureter smooth muscle is set by Ca sparks and BK channels

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  • A Corrigendum to this article was published on 08 September 2005

Abstract

In excitable tissues the refractory period is a critical control mechanism preventing hyperactivity and undesirable tetani, by preventing subsequent stimuli eliciting action potentials and Ca2+ entry. In ureteric smooth muscle, peristaltic waves that occur as invading pacemaker potentials produce long-lasting action potentials (300–800 ms) and extraordinarily long (more than 10 s) refractory periods1,2,3,4,5,6, which prevent urine reflux and kidney damage2. For smooth muscles neither the mechanisms underlying the refractory period nor the link between excitability and refractoriness are properly understood. Here we show that a negative feedback process, which depends on Ca2+ loading the sarcoplasmic reticulum (SR) during the action potential and on the subsequent activation of local releases of Ca2+ from the SR (sparks7), stimulating plasmalemmal Ca2+-sensitive K+ (BK) channels, determines the refractory period of the action potential. As sparks gradually reduce the Ca2+ load in the SR, electrical inhibition is released, the refractory period is terminated and peristaltic contractions occur again. The refractory period can be manipulated, for example from 10 s to 100 s, by altering the Ca2+ content of the SR or release mechanism or by inhibiting BK channels. This insight into the control of excitability and hence function provides a focus for therapies directed at pathologies of smooth muscle.

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Figure 1: Refractory period in intact guinea-pig ureteric smooth muscle.
Figure 2: Effects of stimulus interval on Ca 2+ current.
Figure 3: Ca 2+ sparks, STOCs and the refractory period.
Figure 4: Modulation of the refractory period.

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Acknowledgements

We thank D. Eisner and J. McCarron for discussions, and A. Shmygol and L. Borisova for technical help. Funding was provided by the MRC.

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Correspondence to T. Burdyga.

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Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Video S1

Pseudo-colour images of Ca2+ transients in intact, Fluo-4 loaded guinea- pig ureter, evoked every 10s by suprathreshold depolarising pulses. (MOV 2858 kb)

Supplementary Video S2

An example of real-time grey colour images of Ca2+ sparks, which are discharged at frequent discharging sites located mainly at the edge of the cell membrane of individual smooth muscle cells. (MOV 1340 kb)

Supplementary Video S1 Legend

Legend to accompany this video. (PPT 134 kb)

Supplementary Video S2 Legend

Legend to accompany this video. (PPT 102 kb)

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Burdyga, T., Wray, S. Action potential refractory period in ureter smooth muscle is set by Ca sparks and BK channels. Nature 436, 559–562 (2005) doi:10.1038/nature03834

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