Stephen Sims

Professor

Stephen Sims

PH.D. McMaster University
B.Sc. University of Western Ontario
Office:  Dental Sciences Building 0073
Phone: (519) 661-2111 Ext. 83768
Fax:  (519) 661-3827
E-mail: stephen.sims@schulich.uwo.ca
See Publications by Stephen Sims on PubMed

My studies are focused on transmitter regulation of currents in mammalian smooth muscle. Using the perforated patch configuration of patch-clamp, we record membrane currents from smooth muscle cells while simultaneously monitoring contraction. The excitatory neurotransmitter acetylcholine (ACh) activates non-selective cation and Cl- currents, and also causes contraction, even in the absence of external Ca2+, indicating that ACh causes release of Ca2+ from internal stores, triggering contraction and activating channels. Using Ca2+-sensitive fluorescent dyes, we record membrane currents, [Ca2+]i and contraction simultaneously in single cells.

We are taking an integrative approach to investigate cellular and molecular aspects of signaling in human esophageal smooth muscle (see video panels illustrating contraction above). Experimental approaches include monitoring muscle contraction to investigate regulation of the intact tissues, molecular methods to reveal details of receptors and ion channels, and preparation of dispersed cells to characterize membrane currents and Ca2+ -handling in cells. Our studies represent the first ever study of human esophageal muscle using these multiple approaches. These studies contribute to our understanding of smooth muscle contraction, with relevance to understanding the basis of various smooth muscle disorders, such as gastrointestinal dysmotility and asthma.

Recent studies have investigated Ca2+ sparks in smooth muscle cells. In addition to changes of global [Ca2+]i, as described above, it is now recognized that Ca2+ is a local cytosolic messenger, controlling processes such as contraction, secretion and gene expression. Transient, localized elevations of [Ca2+], referred to as Ca2+ sparks, occur in smooth muscle and are of interest as they regulate the opening of channels, and therefore regulate membrane potential. It is established that sparks cause opening of Ca2+-dependent K+ (KCa) channels, causing hyperpolarization. However, controversy exists concerning the hypothesis that Ca2+ sparks mediate relaxation, as many muscles also exhibit Ca2+-dependent Cl- channels, which contribute to depolarization and excitation. We have shown that tracheal and vascular muscle cells exhibit spontaneous outward K+ currents (STOCs), spontaneous transient inward Cl- currents (STICs) and biphasic currents (STOICs). In collaboration with scientists at the University of Massachusetts, using rapid digital fluorescence imaging microscopy, we demonstrated for the first time that Ca2+ sparks underlie STICs STOCs and STOICs (ZhuGe et al. Journal of Physiology, 513.3:711, 1998).

Other studies use patch-clamp methods to characterize K+ and C1- channels in osteoclasts, the cells responsible for resorption of bone. Just as knowledge of ionic currents is essential for understanding the physiology and pathology of nerve and muscle, such information is instrumental for understanding osteoclasts and resorption of bone. By directly measuring membrane currents we can explore the mechanism of action of agents such as calcitonin and bisphosphonates that are used clinically to reduce bone resorption in diseases such as osteoporosis.

Williams BA, Liu C, De Young L, Brock GB, Sims SM. Regulation of intracellular Ca2+-release in corpus cavernosum smooth muscle: Synergism between nitric oxide and cGMP. American Journal of Physiology (Cell and Molecular Physiology). 288: C650-658, 2005.

Komarova SV, Pereverzev A, Shum JW, Sims SM, Dixon SJ. Convergent signaling by acidosis and receptor activator of NF-kB ligand (RANKL) on the calcium/calcineurin/NFAT pathway in osteoclasts. Proceedings of the National Academy of Sciences U S A, 102: 2643-2648, 2005.

Jones DH, Nakashima T, Sanchez OH, Kozieradzki I, Komarova SV, Sarosi I, Morony S, Rubin E, Sarao R, Hojilla CV, Komnenovic V, Kong YY, Schreiber M, Dixon SJ, Sims SM, Khokha R, Wada T, Penninger JM. Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440: 692-696, 2006.

Sathish V, Xu A, Karmazyn M, Sims SM, Narayanan N. Mechanistic basis of differences in Ca2+-handling properties of sarcoplasmic reticulum in right and left ventricles of normal rat myocardium. American Journal of Physiology (Heart and Circulation), 291: H88-96, 2006.

Kovac JR, Chrones T, Preiksaitis HG, Sims SM. Tachykinin receptor expression and function in human esophageal smooth muscle. Journal of Pharmacology and Experimental Therapeutics 318: 513-520, 2006.




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