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Bioscience Horizons Advance Access published online on April 23, 2008
Bioscience Horizons, doi:10.1093/biohorizons/hzn013
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© Oxford University Press 2008

Sphingosine-1-phosphate activation of TRPC5 in vascular smooth muscle cells

Samantha Fahy

University of Leeds, Leeds, UK

Supervisor: Prof. David Beech, Institute of Membrane and Systems Biology, University of Leeds, Leeds, UK.


  Abstract

Calcium signalling is a complex and diverse system utilized in many cellular processes and in the transmission of cellular information. A number of transient receptor potential (TRP) proteins have been identified in humans and other mammals; these proteins are implicated as having a role in calcium signalling. TRPC5 is a member of this protein family which combines with TRPC1 to form non-selective cation channels in human saphenous vein cells, a type of smooth muscle cell. The exact function of TRPC5 remains elusive, however, it can be activated by sphingosine-1-phosphate (S1P), an endogenous signalling phospholipid involved in SMC migration.

The aim of these experiments was to investigate the effects of S1P on the intracellular calcium concentration, [Ca2+]i, in HSV cells, utilizing dominant-negative (DN)-TRPC5 transfected cells to establish the role played by TRPC5 in this response. A secondary aim was to establish the effect of SMC migration on the above response parameters to S1P using the HSV scratch assay, where a ~2 mm line of cells was scraped away from the surface of a glass cover slip and the remaining cells incubated for 24 h.

Concurrent with the literature, S1P evoked a significant response in HSV cells (n=23; P=0.001). The baseline was significantly lower in the DN-TRPC5 cells compared with the control cells (P<0.001), and the maximum response in the DN-TRPC5 transfected HSV cells reached only 60% of the maximum response in control cells. This suggested that TRPC5 was involved with maintaining basal [Ca2+]i levels and indicated the proportion of the response for which TRPC5 was responsible.

The response to S1P was significantly larger in migrated (n=7) compared with static (n=11) HSV cells (P=<0.001) and this response was delayed by ~2.3 min; the baseline was also higher in the latter group. This suggested a functional change in the cell following migration that may have been attributable to TRPC5, for example, channel up-regulation.

In conclusion, TRPC5-like channels are responsible for a proportion of the S1P response and are implicated in SMC migration. This highlights potential pharmacological targets for the treatment of atherosclerosis, neointimal hyperplasia and coronary heart disease.

Key words: TRPC5, S1P, saphenous, Fura-2, calcium

Submitted on 17 January 2008; accepted on 11 February 2008


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