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NEUROREGULATION AND MOTILITY

Temporal and spatial dynamics underlying capacitative calcium entry in human colonic smooth muscle

Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada

Submitted 6 July 2007 ; accepted in final form 31 October 2007

Following smooth muscle excitation and contraction, depletion of intracellular Ca²⁺ stores activates capacitative Ca²⁺ entry (CCE) to replenish stores and sustain cytoplasmic Ca²⁺ (Ca²⁺_i) elevations. The objectives of the present study were to characterize CCE and the Ca²⁺_i dynamics underlying human colonic smooth muscle contraction by using tension recordings, fluorescent Ca²⁺-indicator dyes, and patch-clamp electrophysiology. The neurotransmitter acetylcholine (ACh) contracted tissue strips and, in freshly isolated colonic smooth muscle cells (SMCs), caused elevation of Ca²⁺_i as well as activation of nonselective cation currents. To deplete Ca²⁺_i stores, the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibitors thapsigargin and cyclopiazonic acid were added to a Ca²⁺-free bathing solution. Under these conditions, addition of extracellular Ca²⁺ (3 mM) elicited increased tension that was inhibited by the cation channel blockers SKF-96365 (10 µM) and lanthanum (100 µM), suggestive of CCE. In a separate series of experiments on isolated SMCs, SERCA inhibition generated a gradual and sustained inward current. When combined with high-speed Ca²⁺-imaging techniques, the CCE-evoked rise of Ca²⁺_i was associated with inward currents carrying Ca²⁺ that were inhibited by SKF-96365. Regional specializations in Ca²⁺ influx and handling during CCE were observed. Distinct "hotspot" regions of Ca²⁺ rise and plateau were evident in 70% of cells, a feature not previously recognized in smooth muscle. We propose that store-operated Ca²⁺ entry occurs in hotspots contributing to localized Ca²⁺ elevations in human colonic smooth muscle.

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