Mechano-electric feedback at cell and tissue level
E. White*
Institute of Membrane and Systems Biology, University of Leeds, Leeds, United Kingdom
Mechanical stimulation, in the form of increasing sarcomere length, influences the contractile activity of the heart (Starling’s Law). Additionally, changes in mechanical state influence both heart rate (the Bainbridge effect) and rhythm, such that acute stretch can trigger arrhythmias, while chronic pressure or volume overload can lead to pro-arrhythmic remodelling.
Multiple, inter-related mechanisms are implicated in these responses and changes that occur in these various parameters under disease conditions are not well understood. This had led to a situation where, in both tissue and single cells, stretch-activated events can be provoked (and attenuated by pharmacological agents) but where the precise mechanisms of action have eluded discovery.
A major factor is the difficulty in defining and measuring the mechanical stimulus itself. For example, it is argued that targets such as mechanosensitive ion channels (MSCs) are regulated by tension in the lipid bilayer. The cytoskeleton may also influence events by transmitting or buffering tension changes to these channels. Recent evidence also suggests regulation of MSCs may result as a secondary event to mechanical activation of signalling pathways e.g. due to mechanically-induced generation of reactive oxygen species.
The identification of MSCs has proven difficult, beyond K+-selective and non-selective cationic sub-types. There seems to be species and tissue differences in the relative important of candidate channels which include, two-pore K+ channels such as TREK-1 and TRPC-channels (type 1,3 and 6). Mechanical modulation of intracellular ion concentrations (Ca2+, Na+, H+) may also influence electrogenic exchangers e.g. Na/Ca exchange. Currently available pharmacological tools preclude detailed mechanistic characterization either because of poor specificity (e.g. Gd3+) or mode of action (e.g. amphipaths). In addition, regional variations, in structure and gene expression, within the ventricles mean that dilation and the response to it will not be homogeneous, thus stretch will modulate the inherent heterogeneity that exists in the ventricles.
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